The multifaceted role of PUMA in cell death pathways: its therapeutic potential across cancer types

Abstract

Abstract

Cell death is a fundamental process essential to all living organisms, with apoptosis serving as one of the most crucial pathways across various stages of life. Dysregulation of apoptosis is closely associated with numerous diseases, particularly cancer. PUMA (p53 upregulated modulator of apoptosis) is a key mediator of apoptotic cell death. It is activated in response to a wide range of internal and external signals. Beyond its established role in apoptosis, PUMA also regulates other forms of cell death, including necroptosis, autophagy, and ferroptosis, underscoring its critical role in cancer cell death, especially during chemotherapy. However, PUMA activation is frequently impaired in many cancers, leading to resistance to cell death and treatment failure. This review highlights recent advancements in understanding the regulation of PUMA expression at multiple levels, including epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms. It also examines the influence of diverse cellular regulators, such as epigenetic modifiers, transcription factors, non-coding RNAs, kinases, and ubiquitin ligases in modulating PUMA activity. Additionally, we discuss PUMA’s role in cancer progression, its impact on the effectiveness of anti-cancer therapies, and its potential as a prognostic biomarker for therapeutic resistance. Finally, we propose critical questions to inspire future research, aiming to deepen the understanding of PUMA regulation and its significance in cancer therapy.

Graphical abstract

The diagram highlights the regulatory network of p53 under stress conditions such as DNA damage, hypoxia, or oncogenic stress. In normal conditions, MDM2 binds to and sequesters p53, leading to its proteasomal degradation. Stress signals activate p53, inducing the pro-apoptotic protein PUMA, which inhibits anti-apoptotic proteins (BCL-2, BCL-XL, and BCL-W), thereby activating the effector proteins BAX and BAK. This activation results in mitochondrial outer membrane permeabilization (MOMP) and cytochrome c (Cyt c) release, triggering caspase activation and apoptosis. Proper apoptosis maintains tissue homeostasis, whereas alterations in this pathway can lead to uncontrolled cell proliferation and cancer.

Introduction

All living organisms adhere to the fundamental law of nature: life and death. Death is inevitable and plays a crucial role in maintaining the balance of ecosystems. In multicellular organisms, the meticulous regulation of cell proliferation and cell death is essential for preserving tissue homeostasis [1]. A cell can experience different forms of cell death, but the most widely recognized types are apoptosis, necrosis and autophagic cell death. Among these, apoptosis is a major form of programmed cell death that plays a pivotal role in various physiological processes, including embryogenesis, organ development, and the immune response to foreign invaders [2, 3]. Given its significance, the dysregulation of apoptosis is often linked to the development of numerous pathophysiological disorders, such as neurodegenerative diseases and cancer [2, 4] (Fig. 1).

Fig. 1.

Dysregulation of apoptosis is linked to a range of diseases

The process of apoptosis is tightly regulated through intricate crosstalk between pro-apoptotic and anti-apoptotic proteins. Dysregulation of apoptosis often occurs due to the inactivation of pro-apoptotic proteins, the overactivation of anti-apoptotic proteins, or a combination of both. One key mechanism underlying impaired apoptosis is the sequestration of pro-apoptotic proteins by anti-apoptotic proteins. Therefore, the delicate balance between these opposing protein groups ultimately determines whether a cell survives or undergoes programmed cell death.

Bcl-2 (B-cell lymphoma 2) was the first anti-apoptotic protein identified in patients with B-cell lymphoma [5]. Since its discovery, other pro-apoptotic and anti-apoptotic proteins have been categorized as members of the Bcl-2 family based on the presence of Bcl-2 homology (BH) domains. All anti-apoptotic proteins in the Bcl-2 family contain four BH domains: BH1, BH2, BH3, and BH4. In contrast, pro-apoptotic proteins are divided into two groups based on their domain composition. Some pro-apoptotic proteins possess multiple BH domains (combinations of BH1, BH2, BH3, and BH4), while others have only the BH3 domain. Pro-apoptotic proteins with multiple BH domains include BAX, BAK, BOK, BCL-XB, and BCL-XS. Those with only the BH3 domain, often referred to as “BH3-only” proteins, include Bid, Noxa, and PUMA.

PUMA (p53 up-regulated modulator of apoptosis) is a key mediator of apoptosis [6, 7]. It interacts with all anti-apoptotic proteins in the Bcl-2 family to promote apoptosis. Furthermore, recent studies have revealed that PUMA also plays a critical role in regulating other cell death pathways, including necrosis, autophagic cell death, necroptosis, and ferroptosis [8–10]. It facilitates cross-talk between these pathways, allowing the type of cell death to be determined by the severity of extracellular or intracellular stress-induced stimuli. Mouse genetic ablation studies have demonstrated that PUMA is a primary mediator of cell death in response to various apoptotic triggers, such as ionizing radiation (IR), deregulated c-Myc expression, and cytokine withdrawal [11]. Studies have shown that PUMA is crucial for stress-induced hematopoietic cell death in both p53-dependent and p53-independent apoptotic pathways. Additionally, PUMA plays a vital role in preventing c-Myc-mediated malignant transformation. Notably, cells lacking PUMA exhibit defects in c-Myc-induced apoptotic cell death, highlighting its essential function in regulating this process [11, 12].

PUMA is a key effector in the induction of apoptosis. However, its cell death activity is often compromised in various types of cancer due to the deregulation of multiple factors [13, 14]. Among these, p53 mutations play a pivotal role in diminishing PUMA activity. Consequently, the efficacy of anti-cancer chemotherapeutic drugs is closely linked to the p53 mutation status [15]. Cancer cells with p53 mutants are severely compromised towards inducing cell death by anti-cancer chemotherapeutic drugs [16, 17]. These p53 mutants are defective in inducing cell death through the induction of apoptotic proteins like PUMA. Rather, it is observed that these p53 mutants play an oncogenic function and are closely associated with increased malignancy, early onset of relapse as well as resistance to anti-cancer drug treatment. Therefore, induction of PUMA could be an effective therapeutic strategy to increase anti-cancer chemotherapeutic drug treatment-mediated efficient induction of apoptotic cell death in p53 wild-type as well as p53 mutated cells.

This review explores recent advances in understanding the mechanisms underlying PUMA regulation at various levels. We highlight its critical involvement in multiple cell death pathways and its role in cancer progression. Additionally, we discuss the relationship between PUMA expression and the therapeutic efficacy of different anti-cancer chemotherapeutic agents.

Structure of PUMA

BBC3 (Bcl-2-binding component 3; PUMA) is located on chromosome 19 in the human genome and consists of four exons [6, 7]. It has been reported that BBC3 encodes α, β, γ, and δ isoforms through alternative splicing [6, 18, 19]. Among these isoforms, the α and β variants contain the BH3 domain and function similarly as pro-apoptotic proteins (Fig. 2).

Fig. 2.

Schematic representation of the genomic structure of PUMA and alternative transcripts. BBC3 (PUMA) is located on chromosome 19 and encodes four isoforms through alternative splicing. PUMA comprises a BH3 domain (containing conserved LRRRMADDLN sequence) and a C-terminal hydrophobic domain with a mitochondrial localization signal (MLS), both crucial for its pro-apoptotic function

Despite several efforts to determine the crystal structure of PUMA, only a partial structure has been resolved using X-ray crystallography. Predictions from AlphaFold suggest that PUMA contains several disordered regions, specifically spanning amino acids 1–28 and 71–138. These disordered regions may contribute to the challenges in resolving its full-length crystal structure. Structurally, PUMA contains a BH3 domain and a C-terminal hydrophobic domain that includes a mitochondrial localization signal (MLS) [6, 7]. The BH3 domain forms an amphipathic α-helical structure, which directly interacts with anti-apoptotic Bcl-2 family proteins [20]. Both the BH3 and MLS domains are essential for PUMA-induced apoptosis, highlighting their critical role in its pro-apoptotic function [21, 22].

Regulation of PUMA

Initially, PUMA was discovered to be transcriptionally regulated by the tumor suppressor p53. However, subsequent studies revealed that PUMA expression is controlled at multiple levels, including transcriptional (Fig. 3A), post-transcriptional (Fig. 3B), and post-translational (Fig. 3C) levels. Among these, the transcriptional regulation of PUMA has been the most extensively studied and is well-documented. In the following sections, we provide a detailed discussion of the mechanisms underlying the transcriptional, post-transcriptional, and post-translational regulation of PUMA.

Fig. 3.

Regulation of PUMA at different levels. Regulation of PUMA occurs at multiple levels: (A) transcriptional, (B) post-transcriptional, and (C) post-translational. Several factors are associated with each of these complex regulation processes. Each of these regulatory layers contributes to the precise control of PUMA, influencing its role in apoptosis and cellular responses to stress

Transcriptional regulation of PUMA

PUMA has minimal expression under normal unstressed conditions. However, its expression level increases sharply at the mRNA level in response to a wide range of extracellular or intracellular stresses.

Transcriptional activation of PUMA

PUMA was first identified as a transcriptional target of the tumor suppressor p53 [6, 7]. p53-mediated transcriptional activation of PUMA has been extensively studied. p53 plays a key role in upregulating PUMA transcription in response to genotoxic and other types of cellular stresses. p53 is responsible for transcriptional upregulation of PUMA in response to genotoxic stresses as well as other types of stresses. Under conditions of severe genotoxic stress, activated p53 promotes apoptosis-driven cell death by inducing PUMA expression at the transcriptional level [6, 23]. Interestingly, p53 can also transcriptionally repress PUMA expression to protect hematopoietic progenitor cells from lethal doses of γ-radiation, demonstrating its dual regulatory role [24].

In addition to p53, several other transcription factors like p63 [25], p73 [26], Sp1 [27], FOXO3a [28], E2F1 [29], CHOP [30], TRB3 (tribbles-related protein 3) [31], AP-1 [30] and c-Myc [12, 32] regulate the expression of PUMA at the transcriptional level [4]. For example, the forkhead family member FOXO3a mediates the transcriptional activation of PUMA in response to cytokine or growth factor withdrawal [28]. However, this regulation by FOXO3a is antagonized by the PI3K/AKT signaling pathway. PI3K/AKT phosphorylates FOXO3a, thereby preventing its recruitment to the PUMA promoter. Additionally, c-Myc impairs the recruitment of FOXO3a to the PUMA promoter by deacetylating histones, further inhibiting PUMA transcription [32].

In addition to well-characterized transcription factors, the C2H2 zinc finger protein PATZ1 has been reported to induce apoptosis in glioblastoma progression by transcriptionally activating PUMA. However, the precise mechanism by which PATZ1 regulates PUMA expression remains unclear [33]. PUMA is also transcriptionally induced in response to endoplasmic reticulum (ER) stress across various cell types. This induction is largely p53-independent and involves other transcription factors such as p63, CHOP, E2F1, and TRB3, which play critical roles in regulating PUMA expression during ER stress [30, 31]. Similarly, p73 and Sp1 cooperate to enhance PUMA expression in response to serum starvation [34].

In addition to transcription factors, certain viral infections can also induce PUMA expression to trigger apoptosis in host cells. For example, the Semliki Forest virus (an RNA virus) and herpes simplex virus 1 (HSV-1) have been shown to regulate intrinsic apoptosis through the modulation of PUMA expression [35].

Transcriptional repression of PUMA expression by transcription factors

In addition to positive transcriptional regulators, several transcription factors suppress PUMA expression to protect cells in specific contexts. For example, transcription factors such as C/EBPβ, CREB, and c-Jun play a critical role in repressing PUMA expression to maintain hepatocyte homeostasis during deoxycholic acid treatment [36]. Interestingly, p53, a well-known positive regulator of PUMA, can also act as a negative regulator in certain contexts by activating SLUG. This mechanism prevents cell death in bone marrow hematopoietic progenitor cells [24]. Specifically, in response to a lethal dose of γ-radiation, p53 transcriptionally activates SLUG, which then represses PUMA expression by directly binding to the PUMA promoter. SLUG effectively inhibits p53-mediated transcriptional activation of PUMA, preventing apoptosis in these cells.

Transcriptional repression of PUMA expression by epigenetic modification

Previous studies have shown that the transcriptional regulation of PUMA is also influenced by epigenetic mechanisms, including histone modifications and DNA methylation of the PUMA promoter [37]. For example, the Enhancer of Zeste Homolog 2 (EZH2), which is highly overexpressed in non-small cell lung cancer (NSCLC), suppresses PUMA expression through the polycomb repressive complex 2 (PRC2) [38]. EZH2 directly binds to the PUMA promoter and recruits other PRC2 components to silence its expression epigenetically. This recruitment leads to an increase in gene-silencing histone marks, such as H3K27me3, and a reduction in activation marks, such as H3K9ac.

In addition to histone modifications, DNA methylation of CpG islands plays a critical role in the reduced expression of PUMA in Burkitt lymphoma [37]. CpG islands are distributed across the promoter, exons, and introns of PUMA, with the CpG island in exon 2 being particularly important for the DNA methylation-mediated epigenetic silencing of PUMA.

Furthermore, the transcription factor Myc has been shown to repress PUMA expression through epigenetic mechanisms. Myc impairs the recruitment of FOXO3a to the PUMA promoter by altering histone modification [32]. Specifically, Myc’s recruitment to the PUMA promoter is associated with increased levels of H3K9me2 and decreased acetylation of H3 and H4 histones. However, the detailed molecular mechanisms underlying Myc-induced increases in H3K9me2 and histone deacetylation remain unclear.

Signalling pathway associated with transcriptional regulation of PUMA

Previous studies have shown that glycogen synthase kinase-3 (GSK-3) plays a crucial role in p53-mediated apoptosis by activating PUMA [39–41]. GSK-3 phosphorylates the acetyltransferase TIP60 at Ser86, which then acetylates p53. Acetylated p53 transcriptionally activates PUMA, promoting efficient apoptotic cell death.

Growth factors activate several signaling pathways, including PI3K-AKT, to facilitate cell proliferation. When growth factors are withdrawn, apoptosis is triggered. The GSK-3 pathway is central to this process, promoting apoptotic cell death through PUMA activation via p53 and FOXO3a during growth factor withdrawal [42].

While GSK-3 activation and PUMA induction are beneficial for cell death under stress, this is not always the case. For example, saturated fatty acids like palmitate can induce hepatocyte lipoapoptosis. Palmitate activates GSK-3, which in turn activates JNK. Activated JNK induces PUMA-mediated lipoapoptosis in hepatocytes [43], highlighting the need for precise control of GSK-3 to prevent this harmful outcome.

Beyond transcriptional activation, GSK-3 also regulates PUMA at the post-translational level. The F-box protein FBXL20 targets PUMA for proteasomal degradation [44]. However, when GSK-3 is activated, it promotes the proteasomal degradation of FBXL20, leading to increased PUMA-mediated apoptosis.

Regulation of PUMA at the post-transcriptional level

MicroRNAs (miRNAs) play a critical role in normal development by regulating various biological processes through controlling the expression of several genes. Therefore, aberrant expression of miRNAs is closely associated with various diseases, including cancer. Like other genes, the expression of PUMA is also regulated by several miRNAs at the post-transcriptional level. For the first time, it was reported that miR-BART5, expressed by the Epstein-Barr virus, suppresses the expression of PUMA to promote the proliferation of host cells [45].

Then, several studies showed that miR-221 and miR-222 facilitate cancer progression and metastasis of several types of cancer cells by attenuating PUMA expression through 3’ UTR binding [46]. Similarly, miR-663 suppresses PUMA expression to promote NSCLC [47], while highly expressed miR-3196prevents apoptotic cell death by repressing PUMA expression [48]. Another study showed that highly expressed miR-494 suppresses PUMA through binding to its 3’ UTR in lung squamous cell carcinoma [49].

In neuroblastoma, miR-483-3p promotes malignancy by negatively controlling PUMA expression [50]. In prostate cancer, miR-125b promotes tumor growth by suppressing several pro-apoptotic proteins, including PUMA [51, 52]. Further studies showed that miR-125b is also highly expressed in ovarian, colon, and pancreatic cancers and suppresses PUMA levels in these cancers. In addition to promoting cancer cell growth, miRNA-mediated suppression of PUMA has also been linked to drug resistance in cancer cells [53].

Grieco et al. showed that downregulation of miR-23a-3p and miR-23b-3p in pancreatic β-cells results in PUMA upregulation and cell death [54]. Moreover, miRNA-mediated deregulation of PUMA is associated with other diseases, such as fetal alcohol spectrum disorder (FASD), non-alcoholic fatty liver disease (NAFLD), type I diabetes mellitus, and brain injuries. For example, Chen et al. showed that miR-125b suppresses PUMA expression, contributing to the development of FASD [55]. They found that ethanol treatment reduced miR-125b levels, leading to PUMA upregulation and apoptosis in neural crest cells [53].

In contrast to miRNAs, long noncoding RNAs (lncRNAs) can increase PUMA expression in various cells. Mechanistically, it is reported that lncRNAs increase the PUMA expression either by increasing the stability of PUMA mRNA or by decreasing the mRNA activity. Du et al. showed that the lncRNA TSLC8 inhibits colorectal cancer cell proliferation by stabilizing PUMA mRNA [56]. In contrast, Zhou et al. demonstrated that the lncRNA GAS5 promotes PUMA stabilization under hypoxic conditions in cerebral ischemia by impairing miR-221-mediated PUMA downregulation [57]. Given the pivotal role of PUMA in regulating cell death, understanding how miRNAs and lncRNAs modulate its expression could offer new therapeutic avenues. Therefore, future studies are needed to develop selective miRNA or lncRNA-based therapies to treat cancer.

Post-translational regulation of PUMA

PUMA expression is typically low under non-stress proliferative conditions, where it is subject to proteasomal degradation [6]. In addition to transcriptional and post-transcriptional regulation, PUMA is also regulated at the post-translational level. Recent studies have highlighted that PUMA is degraded through proteasomal and lysosomal pathways. For instance, Fricker et al. demonstrated that PUMA is phosphorylated in response to serum starvation and interleukin-3 (IL-3) stimulation. They identified multiple serine phosphorylation sites on PUMA (Ser-9, Ser-10, Ser-36, Ser-96, Ser-106, and Ser-166), with Ser-10 being the primary site of phosphorylation [58]. Notably, all these phosphorylation sites, except for Ser-166, lie upstream of the BH3 domain and the C-terminal mitochondria localization signal domain. Ser-166 is located at the C-terminus of PUMA. Phosphorylation at Ser-10 is particularly important proteasomal degradation of PUMA, represses PUMA-induced cell death, and enhances cell survival. In line with this, Sandow et al. showed that the IKKα/IKKβ/NEMO kinase complex also phosphorylates PUMA at Ser-10 in response to IL-3 stimulation to facilitate its proteasomal degradation [59].

In addition to serine phosphorylation, PUMA has been shown to undergo phosphorylation at multiple tyrosine residues [68]. It is reported that HER2 phosphorylates all three tyrosine residues of PUMA to attenuate its expression in HER2-expressing breast cancer. Thus, HER2 promotes cell survival of HER2-positive breast cancer cells by suppressing PUMA expression [60].

Collectively, preceding studies illustrate that multiple kinases phosphorylate PUMA to direct its attenuation at the post-translational level through proteasome. However, the specific E3 ubiquitin ligase responsible for PUMA’s proteasomal degradation remained unidentified until recently. Our study identified the SCF^FBXL20 (SKP1, Cullin 1, and F-box protein complex) as the E3 ubiquitin ligase involved in PUMA degradation through the 26 S proteasome in an AKT-dependent manner. We demonstrated that the F-box protein FBXL20 recognizes the AKT1-mediated phosphorylated form of PUMA (pPUMA-Ser10) and promotes its polyubiquitination to direct proteasomal degradation [44]. Additionally, we showed that AKT1 plays a key role in preventing the proteasomal degradation of FBXL20 by inactivating GSK-3 kinase, which ultimately increases the turnover of PUMA. Notably, analysis of breast cancer patient samples revealed an inverse correlation between the expression levels of PUMA and FBXL20, further supporting this regulatory mechanism. These findings provide a comprehensive understanding of the post-translational regulation of PUMA and its degradation through the AKT-dependent SCF^FBXL20 pathway. Interestingly, a previous study showed that p53 positively regulates FBXL20 upon DNA damage to prevent autophagy induction [61]. Further, p53 is known to be transcriptionally active PUMA. In contrast, we found that FBXL20 directs the degradation of PUMA under unstress conditions without affecting its transcriptional level, indicating that p53 may not be involved in FBXL20-mediated attenuation of PUMA.

Role of PUMA in different types of cell death

Cell death occurs through two main processes: accidental cell death (ACD) and regulated cell death (RCD). RCD can be further classified into caspase-dependent cell death, such as apoptosis and pyroptosis, and caspase-independent forms of RCD, including autophagic cell death, necroptosis, ferroptosis, parthanatos, alkaliptosis, and oxeiptosis [62]. In addition to apoptotic cell death, recent studies have emphasized the significant role of various non-apoptotic forms of cell death in the progression of several human diseases [62].

PUMA is a crucial mediator of apoptosis

PUMA plays a pivotal role in inducing apoptotic cell death through the intrinsic pathway. A key mediator of this process is p53, whose anti-proliferative activity in response to various stimuli largely relies on the induction of apoptosis. p53 contributes to the effective execution of cell death by enhancing PUMA expression through both its transcriptional and non-transcriptional activities.

Notably, PUMA-mediated cell death is not exclusively dependent on p53. Other pathways have been identified that can activate PUMA independently of p53, further underscoring PUMA’s versatile role in regulating cell fate. By functioning in both p53-dependent and p53-independent mechanisms, PUMA serves as a critical determinant in deciding whether a cell survives or undergoes apoptosis (Fig. 4).

Fig. 4.

PUMA-mediated apoptosis involves both p53-dependent and independent pathways. (A) In normal conditions, p53 is sequestered by MDM2. Upon DNA damage, accumulated p53 increases PUMA levels, which sequesters anti-apoptotic proteins, leading to the release of effector proteins BAX/BAK. This induces cytochrome c release from mitochondria, triggering apoptosis associated with embryogenesis, tissue homeostasis, and negative selection of autoreactive T cells. (B) p53-independent apoptosis occurs primarily through NF-κB and CHOP during ER stress, FOXO3a upon growth factor withdrawal via the AMPK-mediated pathway, and p73 during DNA damage conditions. (Red lines in Fig. 4A indicate apoptosis-promoting action and black lines indicate apoptosis-inhibiting action)

Crosstalk of PUMA and p53 in apoptosis induction

In response to genotoxic stress, p53 accumulates in both the nucleus and the cytoplasm [63]. It initiates apoptosis through its transcriptional activity in the nucleus and its non-transcriptional functions in the cytoplasm. In the nucleus, p53 upregulates the expression of the pro-apoptotic protein PUMA, which interacts with anti-apoptotic BCL2 family proteins, such as BCL-2, to release BAX and BAK. These released proteins oligomerize on the outer mitochondrial membrane, causing mitochondrial membrane permeabilization and activating caspases.

In the cytoplasm, p53 is sequestered by the anti-apoptotic protein BCL-XL. Upon DNA damage, PUMA accumulates and disrupts the p53-BCL-XL complex [64]. This release allows cytoplasmic p53 to activate BAX, facilitating mitochondrial membrane permeabilization and triggering apoptosis [65]. Therefore, both nuclear and cytoplasmic p53 play essential roles in apoptosis through a PUMA-dependent mechanism (Fig. 4A).

Several proteins, including NEDD8, Cullin 4B (CUL4B), PSMD7, and MAGEA3, are aberrantly overexpressed in cancer cells and contribute to oncogenesis by suppressing p53 activity. Studies have shown that the neddylation pathway promotes tumorigenesis by reducing p53 levels. UBE2M, an E2 NEDD8-conjugating enzyme, is frequently overexpressed in cancer cells and enhances the expression of MDM2. MDM2 interacts with KAP1 to regulate p53 expression [66]. The MDM2/KAP1/HDAC.1 complex inhibits p53 acetylation and promotes its polyubiquitination, leading to proteasomal degradation via the 26 S proteasome. This degradation reduces p53 levels, which in turn decreases PUMA expression, halting apoptosis and promoting uncontrolled proliferation in hepatocellular carcinoma cells.

Additionally, MAGEA3 interacts with KAP1 to prevent p53 acetylation, thereby inhibiting its transcriptional activity. MAGEA3 is upregulated in various cancers and facilitates cell proliferation by suppressing PUMA expression in a p53-dependent manner [67]. CUL4B, a member of the Cullin RING E3 ligase family, also contributes to tumorigenesis and cancer progression. Xiang et al. demonstrated that CUL4B promotes cancer development by attenuating PUMA expression through the proteasomal degradation of p53 [68]. Moreover, the deubiquitinase PSMD7, which is overexpressed in non-small cell lung cancer (NSCLC), promotes tumorigenesis by reducing p53 and PUMA levels [69]. PSMD7 suppresses PUMA expression in a p53-independent manner by interacting with PSMD14, a core component of the 19 S proteasome, to enhance proteasomal activity. These findings highlight the critical role of PUMA and its regulation in apoptosis and underscore the significance of targeting these pathways for potential therapeutic strategies in cancer.

PUMA induces apoptosis in p53 independent manner

PUMA, a key pro-apoptotic protein, plays a crucial role in eliminating damaged cells under various pathological conditions, including ischemia-related disorders such as myocardial infarction and stroke. These conditions often result in irreversible tissue damage. Research has shown that PUMA mediates apoptosis in these damaged cells independently of p53. Several factors, including reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress caused by ATP deficiency, altered calcium levels, and tissue acidosis, contribute to the elevated expression of PUMA. Key transcription factors involved in PUMA activation under these conditions include E2F1, p73, and the ER stress-specific transcription factor C/EBP homologous protein (CHOP) [4].

PUMA activation at the mRNA level has also been observed in p53-independent apoptotic pathways. For instance, tumor necrosis factor-alpha (TNF-α) induces apoptotic cell death in colon cancer by activating the NF-κB signaling pathway. TNF-α facilitates the proteasomal degradation of IκB, allowing the p65 component of NF-κB to translocate to the nucleus, where it directly binds to the PUMA promoter to increase PUMA mRNA levels. Studies have further demonstrated that p53 and p65 can cooperate to induce apoptosis by elevating PUMA expression [70]. Similarly, sorafenib activates PUMA via the NF-κB pathway in a manner that is independent of both p53 and IκB [71]. Additionally, NF-κB-p65 plays a key role in interleukin-6 (IL-6)-driven apoptosis. Mechanistically, IL-6 promotes FASL production, which activates NF-κB-p65 to transcriptionally upregulate PUMA expression (Fig. 4B).

Beyond stress responses, viral infections also elevate PUMA levels to induce apoptosis in host cells. Viruses often impair host antiviral proteins that block caspase activation or mimic BCL-2 to prevent mitochondrial outer membrane permeabilization [35]. Studies have reported increased PUMA levels in human monocytes, mouse embryonic fibroblasts, and colon cancer cells following infection with double-stranded DNA herpes simplex virus-1 (HSV-1) and single-stranded RNA Semliki Forest virus (SFV). Notably, canonical PUMA regulators such as p53, p73, or NF-κB are not involved in virus-induced apoptosis. Instead, post-translational regulation appears to be the primary mechanism driving PUMA activation in virus-infected cells, leading to MOMP and apoptosis. Additionally, transcriptional upregulation of PUMA amplifies the apoptotic cascade following MOMP and caspase-3/-7 activation. In contrast, the V protein of the measles virus inhibits p73 and reduces PUMA levels, delaying apoptosis induced by genotoxic stress [72].

Estrogen has also been shown to transcriptionally downregulate PUMA expression in a p53-independent manner [73]. Interestingly, PUMA is a direct target of estrogen, and this repression occurs independently of the co-repressor SAFB1. However, the precise molecular mechanisms underlying estrogen-mediated PUMA suppression remain to be elucidated.

PUMA is an upstream regulator of caspase activation through cytochrome c release, which occurs via MOMP permeabilization. Intriguingly, caspase-9 and caspase-3 play critical roles in PUMA activation in a p53-independent manner upon treatment with the protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) [74]. Mechanistically, caspase-9 inactivates the anti-apoptotic proteins BCL2 and BCL-XL by promoting their proteasomal degradation and subsequently activates caspase-3. Activated caspase-3 then cleaves the anti-apoptotic protein XIAP, facilitating PUMA activation and inducing apoptotic cell death. However, further research is required to clarify how the inactivation of BCL2, BCL-XL, and XIAP specifically leads to PUMA activation. These findings underscore the diverse regulatory mechanisms and contexts in which PUMA plays a central role in apoptosis, highlighting its potential as a therapeutic target in conditions characterized by excessive or impaired cell death.

Role of PUMA in autophagic cell death

Autophagy maintains cellular homeostasis by degrading and recycling unfolded proteins and damages organelles [75, 76]. During autophagy, damaged and non-functional proteins and organelles are sequestered in the double-membrane autophagosomes that fuse with the lysosomes for subsequent degradation. Autophagic cell death occurs via macroautophagy, microautophagy, or chaperone-mediated autophagy (CMA). During CMA, PUMA is degraded after binding to HSPA8/HSC70, highlighting its dynamic regulation between autophagy and apoptosis [77]. Low PUMA levels during autophagy allow stressed cells to recover, while its degradation during CMA prevents excessive apoptosis [77, 78]. Blocking CMA, however, accelerates apoptosis in tumor cells. Autophagy helps cells to manage stress by recycling nutrients, but its inhibition often triggers apoptosis due to the accumulation of damaged components. This principle is exploited in cancer therapies that block autophagy to sensitize cells to apoptosis. It is reported that FOXO3a regulates basal autophagy and can activate PUMA during autophagy inhibition to promote apoptosis [79].

Mitophagy specifically targets dysfunctional mitochondria for removal. Previous study showed that PUMA plays a key role in mitophagy under mitochondrial stress in osteosarcoma cells [80]. Therefore, blocking PUMA-induced mitophagy reduces apoptotic cell death, highlighting its unique regulatory role [80]. PUMA also regulates aberrant autophagy in amyloid-β-treated neuronal cells by interacting with Beclin1, a mechanism separates from mitophagy [81] (Fig. 5).

Fig. 5.

PUMA regulate different cell death pathways in various conditions. (A) In response to genotoxic and oncogenic stresses, PUMA induces apoptosis in a p53-dependent manner. Accumulated p53 sequesters anti-apoptotic proteins (BCL-2, BCL-XL, BCL-W) and releases pro-apoptotic proteins (BAX, BAK), leading to Cyt c release from mitochondria and caspase-mediated apoptosis. (B) In necroptosis, PUMA is activated by RIP3 (Receptor-interacting protein 3) and MLKL, which induces necroptosis. PUMA also releases Drp1 from BCL-XL, promoting necroptosis. (C) In amyloid-β treated neuronal cells, PUMA triggers aberrant autophagic cell death through interaction with Beclin1. PUMA undergoes proteasomal degradation during chaperone-mediated autophagy, and its inhibition accelerates apoptosis. Autophagy inhibition forces cells with unfolded proteins into apoptosis, while FOXO3a-stimulated PUMA activation facilitates apoptotic cell death. (D) During ferroptosis, PUMA activation is dependent on CHOP, not p53

Role of PUMA in necrosis

Necrosis-mediated cell death occurs in response to injury, hypoxia, or other extracellular stimuli. Unlike apoptosis, necrosis does not require caspase activation and is often accompanied by the release of damage-associated molecular patterns (DAMPs) into the cytoplasm, which elicit an immune response. Interestingly, recent studies have revealed that PUMA plays a pivotal role in necrosis under certain pathological conditions. A previous study suggests that PUMA controls necrosis-mediated cell death in response to Acetaminophen (AP) treatments [82]. While AP is widely used to alleviate minor pain and fever, an overdose can cause necrosis in hepatocytes, leading to liver injury. Mechanistically, AP treatment activates PUMA, which mediates hepatocyte necrosis through a cascade involving serine-threonine kinases RIP1 and JNK. These kinases transcriptionally upregulate PUMA to releases Drp1 from its interaction with BCL-XL. This release facilitates Drp1-mediated mitochondrial dysfunction, culminating in necrotic cell death [82]. Beyond AP-induced hepatocyte necrosis, PUMA has also been implicated in ischemia-reperfusion injury and cardiomyocyte necrosis in mouse models [83] (Fig. 5). These findings suggest a broader role for PUMA in mediating tissue injury beyond apoptotic pathways.

Notably, tumor necrosis is closely associated with tumor metastasis and is often driven by hypoxia and nutrient deprivation in the tumor microenvironment. Hypoxia is known to activate the NF-κB pathway, which may, in turn, activate PUMA to induce necrosis in tumors. However, the precise role of PUMA in tumor necrosis remains to be elucidated, necessitating further investigation.

Collectively, these findings highlight an unconventional role of PUMA in modulating non-apoptotic cell death and tissue injury. Therefore, modulation of PUMA expression could serve as a potential therapeutic strategy to mitigate necrosis-related tissue damage in conditions such as drug-induced liver injury, ischemia-reperfusion injury, and possibly even cancer metastasis.

Role of PUMA in necroptosis

Necroptosis is a unique form of programmed cell death that exhibits morphological similarities to necrosis and mechanistic parallels with apoptosis [84]. Unlike apoptosis, necroptosis elicits a stronger immune response, making it a critical player in inflammation and immune activation [85]. Damage-associated molecular patterns (DAMPs) contribute to the intense proinflammatory nature of necroptosis [86]. The induction of necroptosis depends on two essential serine-threonine kinases, RIP1 and RIP3, which form an amyloid signaling complex known as the “necrosome”. This complex recruits and activates mixed-lineage kinase domain-like protein (MLKL), leading to necroptotic cell death [87].

Recent discoveries have unveiled an unexpected role for PUMA in amplifying necroptotic signaling. PUMA activates DNA sensors such as DAI/Zbp1 and STING, which in turn promote the activation of crucial kinase RIP3 and MLKL [8]. Mechanistically, PUMA facilitates necroptosis in caspase-depleted, RIP3-expressing cells by releasing mitochondrial DNA into the cytoplasm. This cytosolic mitochondrial DNA acts as a DAMP, triggering an innate immune response. Previous study showed that PUMA facilitates 5-fluorouracil-induced necroptotic death in RIP3-expressing colorectal cancer cells through a PUMA-dependent but RIP1-independent pathway [88] (Fig. 5). These studies highlight the importance of PUMA in necroptosis. However, induction of necroptosis has been proposed to have dual roles in cancer progression. While beneficial in the early stages of tumorigenesis by eliminating damaged or cancerous cells, necroptosis may promote cancer progression, metastasis, and immune evasion in later stages [89]. This duality underscores the complexity of necroptosis in cancer biology.

Interestingly, several compounds have been identified that induce necroptotic cell death in apoptosis-resistant cancer cells, suggesting potential therapeutic applications. Therefore, developing necroptosis-inducing drugs could provide a valuable strategy for treating cancers resistant to conventional apoptotic therapies. Therefore, a deeper understanding of the PUMA-necroptosis axis is needed to clarify its role in cancer progression and immune modulation. Unraveling the precise mechanisms by which PUMA controls necroptotic pathways may help pave the way for innovative therapies to target apoptosis-resistant cancers.

Role of in ferroptosis

Ferroptosis is an iron-dependent form of cell death characterized by lipid peroxidation and iron accumulation within dying cells. The term “ferroptosis” was first introduced in 2012 by Brent Stockwell’s group to describe this unique form of cell death [90]. They demonstrated that ferroptosis is genetically regulated and distinct from other cell death processes, such as apoptosis, necrosis, and autophagy. Morphologically, cells undergoing ferroptosis exhibit irregularly shaped, smaller mitochondria with reduced cristae and ruptured plasma membranes, as observed during Erastin-induced ferroptosis [90]. Further research has identified key regulators of ferroptosis, including PUMA and BID, which play crucial roles in its induction [10]. Interestingly, the activation of PUMA in ferroptosis has been found to occur independently of p53 but is dependent on CHOP, a transcription factor involved in stress responses [91] (Fig. 5). Despite these findings, the precise role of PUMA in the ferroptosis process remains unclear, warranting further investigation.

Interplay between different cell death pathways in cancer

These cell death pathways are interconnected, and cancer cells often exploit their regulatory mechanisms to survive, for example, inhibition of apoptosis may sensitize cells to ferroptosis or necroptosis [92, 93]. Autophagy can prevent ferroptosis by removing damaged mitochondria and reducing ROS production [94]. Necroptosis can stimulate an inflammatory response that influences both tumor immunity and progression. Targeting these non-apoptotic pathways has significant therapeutic potential, especially for apoptosis-resistant cancers.

Importance of PUMA in Cancer

PUMA (p53 upregulated modulator of apoptosis) is pivotal in mediating apoptotic cell death across various cancer types. Its expression is often regulated by the p53 pathway and other signaling mechanisms, highlighting its potential as a therapeutic target. This section provides a concise overview of PUMA’s role in different cancers and its therapeutic implications.

General role of PUMA in cancer

PUMA is a critical effector of apoptosis induced by chemotherapeutic agents and radiotherapy. Loss of PUMA function, often due to p53 mutations in cancer, contributes to resistance against these treatments. Consequently, targeting pathways that activate PUMA or compensating for its loss offers promising strategies for enhancing treatment efficacy.

Specific cancers and therapeutic insights

Acute myeloid leukemia (AML)

Aberrant signaling pathways are a hallmark of acute myeloid leukemia (AML). The MAPK/MEK pathway is activated in 80% of primary AML samples, and MEK inhibitors effectively induce apoptosis by upregulating PUMA expression at both mRNA and protein levels [95]. Similarly, MDM2 is overexpressed in 50% of AML cases, and dual inhibition of MAPK and MDM2 significantly enhances PUMA-mediated apoptosis [96]. WTIP, a tumor suppressor, is under-expressed in most AML patients and promotes apoptosis by activating FOXO3a, which subsequently induces PUMA expression. Clinical studies have shown that the dephosphorylation of FOXO3a by azacitidine or decitabine facilitates its nuclear translocation, triggering PUMA-driven apoptotic cell death. This mechanism is particularly relevant for improving treatment outcomes in AML [97–99] (Fig. 6A).

Fig. 6.

Role of PUMA in AML, breast, colon and lung cancer pathogenesis and therapeutic strategies for regulating PUMA expression. (A) In AML, combining AZD6244 (MEK inhibitor) and Nutlin-3a (MDM2 inhibitor) synergistically induces cell death. WTIP, a tumor suppressor deregulated in AML patients, is involved in FOXO3a-mediated PUMA upregulation. (B) In ER-positive breast cancer, estrogen reduces PUMA expression, making tamoxifen a potential therapy to induce PUMA-mediated cell death. HER2 downregulates PUMA, while mTOR inhibitors increase PUMA expression in a FOXO3a-dependent manner. Targeting the c-Src-Slug-PUMA axis and the AKT1-FBXL20 axis can enhance apoptosis. My11 (a chalcone derivative) promotes apoptosis via the NF-κB/PUMA/mitochondrial pathway. (C) Different kinase inhibitors can target colon cancer to promote PUMA-mediated apoptosis. (D) In NSCLC, loss of FHIT (Fragile histidine triad) increases SLUG, which represses PUMA. EZH2 and HEATR1 also repress PUMA. ALK, which activates AKT and reduces PUMA, can be targeted with alectinib, ceritinib, or brigatinib

The clinical relevance of PUMA is further supported by its predictive value in therapy response. High levels of miR-155 are associated with poor prognosis in AML due to PUMA suppression. Mechanistically, miR-155 promotes SLUG expression, which represses PUMA. Targeting miR-155 or SLUG could restore PUMA activity, enhancing apoptosis and improving patient outcomes [100, 101].

PUMA’s role in mediating apoptosis makes it a promising biomarker and therapeutic target in AML. Strategies to upregulate PUMA, either by inhibiting its suppressors (e.g., miR-155, SLUG) or through combination therapies involving MEK and MDM2 inhibitors, could significantly improve the efficacy of existing treatments and benefit AML patients.

Breast cancer

PUMA plays a critical role in mediating apoptotic cell death in breast cancer and is differentially regulated across subtypes. In ER-positive breast cancer, estrogen suppresses PUMA expression via direct binding upstream of its transcription start site, independent of p53. Anti-estrogen therapies like tamoxifen restore PUMA expression, promoting apoptosis and improving treatment outcomes. Similarly, toremifene induces PUMA-mediated apoptosis, although its mechanism remains unclear [73, 102].

HER2 overexpression in 25–30% of breast cancers promote cell survival by phosphorylating PUMA and reducing its stability. HER2 inhibitors rely on PUMA and BIM to enhance apoptosis, making PUMA a key determinant of therapeutic efficacy in this subtype [103, 104].

In TNBC, PUMA mediates apoptosis in response to BH3 mimetics [105], mTOR inhibitors [105] and herbal compounds like curcumol, even in p53-mutant cells. Further, it was found that PUMA plays a critical role in overcoming TNBC’s resistance to standard treatments in combination therapies [106, 107]. Furthermore, it was reported that curcumol suppresses TNBC in a p73-dependent but not p53-dependent manner, highlighting the distinct roles of p73 and p53 in TNBC progression and treatment. Interestingly, p53 is frequently mutated in TNBC. In contrast, p73 is less frequently mutated and can remain functional even in p53-deficient cells [108]. Therefore, p73-mediated PUMA activation can be explored for therapeutic intervention.

PUMA suppresses metastasis by preventing tumor cell colonization at secondary sites. SLUG, a transcriptional repressor of PUMA, promotes metastasis and resistance to radiotherapy. Targeting the Src-SLUG-PUMA axis offers potential for reducing metastatic burden and improving therapy responses [109–114]. Drugs like doxorubicin, cyclophosphamide, and paclitaxel significantly upregulate PUMA, enhancing apoptotic responses in breast cancer. Novel agents such as MY11, goniothalamin (GTN), and benzo(a)pyrene also leverage PUMA to induce apoptosis, highlighting its therapeutic relevance across breast cancer subtypes [115–121]. PUMA’s role as a mediator of apoptosis makes it a crucial biomarker and therapeutic target. Restoring or enhancing PUMA activity, either by inhibiting its repressors (e.g., SLUG) or using PUMA-inducing agents, could improve the efficacy of existing treatments and address drug resistance in breast cancer.

AKT1 is frequently aberrantly activated in breast cancers, where it plays a critical role in suppressing apoptotic cell death. While it was known that AKT1 inhibits GSK3α/β kinase to prevent apoptosis in cancer cells, the precise mechanism underlying AKT1’s anti-apoptotic activity remained unclear for a long time. Subsequent research revealed that AKT1 phosphorylates PUMA, thereby attenuating its pro-apoptotic activity [58].

A recent study has provided a more detailed understanding of AKT1’s anti-apoptotic mechanism [44]. The study demonstrated that AKT1 promotes PUMA degradation by facilitating its polyubiquitination through the F-box protein FBXL20. This process enhances breast cancer malignancy by reducing PUMA levels and thereby suppressing apoptosis. Furthermore, the inactivation of AKT1 was shown to result in the proteasomal degradation of FBXL20 in a GSK3β-dependent manner. Specifically, the F-box protein FBXO31 targets FBXL20 for degradation, leading to the stabilization and activation of PUMA (Fig. 6B).

These findings suggest that the AKT1-FBXL20 axis plays a pivotal role in regulating apoptotic cell death in breast cancer. Targeting this pathway to inhibit AKT1 or FBXL20 could enhance PUMA activation, thereby increasing apoptosis and improving therapeutic outcomes for patients with breast cancer.

Colorectal cancer (CRC)

PUMA plays a significant role in mediating apoptosis in colorectal cancer (CRC), with its expression often suppressed due to genetic and epigenetic alterations. PUMA expression is primarily regulated by p53, which is mutated in 43% of CRC cases [122]. Even in p53 wild-type tumors, factors like TRAF6 and MDM2 disrupt PUMA-mediated apoptosis by inhibiting p53 activity. Thus, inactivation of MDM2 could be an important strategy to induce apoptotic cell death. Indeed, a previous study showed that MDM2 inactivation results in p73-E2F1-mediated PUMA activation even in p53 deficient CRC cells [123].

Therefore, restoring PUMA through MDM2 inhibitors or p73 activation offers a potential therapeutic strategy [122–125]. Epoxomicin enhances PUMA-mediated apoptosis, making it a promising option, particularly in p53-functional CRC [126].

Adriamycin induces apoptotic cell death through the induction of PUMA in a p53-dependent manner. However, it has been reported that Adriamycin also promotes autophagic cell death in colon cancer cells under high-glucose conditions. Mechanistically, homeodomain-interacting protein kinase 2 (HIPK2) phosphorylates p53 at Ser-46, leading to PUMA expression following Adriamycin treatment. However, in the presence of high glucose, HIPK2 undergoes degradation. In contrast, under high-glucose conditions, p53 efficiently induces the expression of the stress-induced regulator of autophagy, DRAM (damage-regulated autophagy modulator), to promote autophagy following Adriamycin treatment. Thus, high-glucose stress conditions shift p53-mediated transcriptional activation from PUMA to DRAM, leading to autophagic cell death upon Adriamycin treatment [127]. However, the molecular mechanisms underlying this transcriptional switch of p53 under high-glucose conditions remain unclear.

Oxaliplatin and capecitabine promote PUMA-driven apoptosis, demonstrating efficacy with reduced toxicity in CRC [128, 129]. Induces apoptosis via PUMA but can switch to autophagy under high-glucose conditions. Understanding this switch may optimize its therapeutic use [127]. miR-503-5p downregulates PUMA, contributing to oxaliplatin resistance. Targeting miR-503-5p may restore chemosensitivity [53]. Fruquintinib, a VEGFR inhibitor, may indirectly enhance PUMA activity by disrupting VEGFR-1-mediated suppression of apoptosis [130–132]. Tazemetostat, an EZH2 inhibitor, activates PUMA and enhances the efficacy of 5-fluorouracil in CRC [133] (Fig. 6C). Hsp90 inhibitors like 17-AAG induce PUMA in a p53-dependent manner, offering potential in targeted therapy [134]. Taurine, a naturally occurring compound, induces PUMA-mediated apoptosis, showcasing the potential of dietary interventions in CRC management [135].

Strategies to upregulate PUMA, either directly or by modulating pathways like VEGFR and MDM2, could enhance the efficacy of current treatments and overcome resistance mechanisms, paving the way for more effective CRC therapies.

Kinase inhibitors in colon cancer

Being a tumor suppressor, the apoptotic function of PUMA is suppressed by multiple oncogenic kinase signalling pathways and therefore inactivation of these signalling pathways initiates apoptosis induction in colon cancer cells [71, 136–138]. It was shown that treatment of colon cancer cells with multi-kinase inhibitor UCN-01 (inhibits CDK, CHK1, PKC, AKT and PDK1) induces apoptosis in PUMA dependent manner [136]. Similarly, the c-MET/ALK inhibitor crizotinib [137], and the multikinase inhibitor drugs Sorafenib [139] and sunitinib [138] also induce PUMA-mediated cell death in colon cancer. The treatment of Sorafenib in colon cancer cells increases glycogen synthase kinase 3β (GSK3β) and ERK activation to increase the level of PUMA. On the contrary, the activation of PUMA by aurora kinase inhibitors depends on the activation canonical NF-κB pathway and AKT inhibition. Further, it is reported that other aurora kinase inhibitors especially (ZM-447439 and VX-680) may function through different transcription factors, such as p73, to up-regulate levels of PUMA and other Bcl-2 family members to induce apoptosis. Thus, PUMA induction might be a useful biomarker for clinical trials testing for aurora kinase inhibitors [140]. Further, it is reported that FMS-like tyrosine kinase 3 inhibitor, gilteritinib, suppresses CRC through PUMA-induced mitochondria-mediated apoptosis in a p53-independent manner [141]. Mechanistically, authors showed that gilteritinib facilitates nuclear translocation of p65 by activating GSK3β through inhibition of AKT kinase activity. In addition, the authors observed that in combination with optimum doses of 5-FU or cisplatin, gilteritinib robustly induces apoptosis through PUMA. The importance of PUMA in CRC treatment was further supported by 5-FU-based adjuvant therapy. It was observed that the presence of PUMA in stage II and III CRC patients receiving adjuvant therapy have better responses and overall survival, and therefore PUMA can provide the prognostic marker [142]. Therefore, induction of PUMA may be a useful surrogate biomarker for colorectal cancer response to gilteritinib [141]. Similarly, cabozantinib, (a small molecular multi-kinase inhibitor of tyrosine kinase C-MET, AXL, and VEGFR2) has been used to treat multiple malignancies including thyroid, renal cell and hepatocellular carcinoma. It also induces PUMA-dependent apoptosis and growth inhibition of CRC by abrogating AKT to activate the p65-dependent signalling pathway. On the other hand, cabozantinib also synergistically induces PUMA-dependent apoptosis in CRC cells in combination with Cetuximab and 5-FU [143]. Idelalisib is a potent inhibitor of p110δ isoform of PI3K and is commonly used in blood cancer. It is reported that idelalisib enhances the expression of PUMA through GSK-3β/NF-κB pathway to induce apoptotic death of colorectal cancer cells. Interestingly, idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via induction of PUMA in colon cancer cells [144].

Osimertinib is a third-generation irreversible EGFR/HER2 tyrosine kinase (EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases) inhibitor and is effective in lung cancer models [145]. In the same year, Guo et al. demonstrated the anticancer activity and molecular mechanism of Osimertinib in CRC cell lines [146]. They found that Osimertinib treatment increases PUMA expression in a p53-independent manner to induce apoptosis in CRC cells. Mechanistically, authors found that Osimertinib treatment mediated increased PUMA expression in CRC cells is controlled by p73 through PI3K/AKT pathway inhibition. In addition, a combination of Osimertinib with 5-FU shows significant anticancer activity by inducing PUMA-regulated apoptosis in CRC cells [146].

Copanlisib, a specific inhibitor of PI3K (pan-class I phosphoinositide 3-kinase) that preferentially inhibits PI3Kδ and PI3Kα, prevents the growth of CRC cells by inducing PUMA-mediated apoptosis in p53-independent but FOXO3a dependent manner [147]. Mechanistically, the authors showed that copanlisib facilitates the recruitment of FOXO3a onto the PUMA promoter to increase PUMA expression upon inactivation of AKT signalling.

Lung cancer (NSCLC)

Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancers and has high mortality rates. PUMA (p53 upregulated modulator of apoptosis) is frequently inactivated in NSCLC, contributing to disease progression and resistance to therapies.

EZH2 overexpression in NSCLC silences PUMA transcription via H3K27 trimethylation. Targeting EZH2 enhances apoptosis and improves cisplatin efficacy, highlighting the potential of epigenetic therapy [71]. Loss of FHIT promotes SLUG upregulation via AKT/NF-κB signaling, repressing PUMA expression and conferring cisplatin resistance. Patients with low FHIT and PUMA levels exhibit poorer clinical outcomes [148]. HEATR1 overexpression suppresses PUMA by controlling ribosome biogenesis. Its depletion activates the p53-PUMA axis, inducing apoptosis [149].

LincRNA-p21 and miR-222-3p repress PUMA expression, facilitating tumor progression. Conversely, miR-203 upregulation by adriamycin enhances PUMA expression and apoptosis [150, 151].

FDA-approved drugs

Gefitinib (EGFR inhibitor): Induces PUMA-mediated apoptosis in EGFR-mutant NSCLC but shows enhanced efficacy when combined with aurora kinase inhibitors [152, 153]. Mechanistically, aurora B inhibition leads to inhibition of phosphorylation at Ser87 phosphorylation of BIM that stabilizes BIM. BIM is then responsible for the transactivation of PUMA to induce apoptotic cell death through FOXO1/3 [153]. In addition, a small molecular inhibitor of the ERK1/2 pathway, propofol, was found to induce p53-dependent PUMA-mediated apoptosis in A549 cells [154].

ALK (Anaplastic lymphoma kinase) Inhibitors: Drugs like alectinib, brigatinib, and ceritinib target ALK activation, restoring PUMA-mediated apoptosis [155, 156].

Bevacizumab (VEGF inhibitor): Enhances PUMA via CHOP activation, suppressing tumor proliferation [157].

Doxorubicin and Afatinib: Promote PUMA-dependent apoptosis through AKT pathway inhibition [157, 158].

Besides the FDA-approved drugs, buparlisib and metformin synergistically activate PUMA through FOXO3a, sensitizing NSCLC cells to apoptosis [159]. Apart from synthetically manufactured chemical drugs, some naturally occurring bioactive compounds have also been reported to induce PUMA-mediated apoptotic cell death in lung cancer cells. Deguelin, Genistein, and Xanthohumol naturally derived compounds enhance PUMA activity by inhibiting the PI3K/AKT pathway, inducing apoptosis in NSCLC cells [160–162] (Fig. 6D). Adenovirus-mediated delivery of PUMA (Ad-PUMA) significantly improves NSCLC cell sensitivity to chemotherapeutic agents like cisplatin and γ-irradiation, suggesting its potential in gene therapy [163].

PUMA serves as a broad-spectrum chemosensitizer and radiosensitizer in NSCLC. Therapeutic strategies aimed at restoring or enhancing PUMA activity, whether through targeted drugs, combination therapies, or natural compounds, hold promise for improving treatment outcomes and overcoming resistance in NSCLC.

PUMA in other cancers: Clinical applications

PUMA (p53 upregulated modulator of apoptosis) is vital in regulating apoptotic cell death across various cancer types, including hematological malignancies and solid tumors. It is frequently suppressed through genetic, epigenetic, and post-transcriptional mechanisms, contributing to cancer progression and therapy resistance. Targeting PUMA pathways holds significant promise for improving therapeutic outcomes in these cancers.

Hematological malignancies

Burkitt’s lymphoma (BL)

Epstein–Barr virus (EBV) suppresses PUMA expression via multiple mechanisms [164–166], including epigenetic silencing [167] and small RNA regulation [168], aiding tumorigenesis. Restoring PUMA with epigenetic drugs like 5-Aza [167] or combining EZH2 degraders with BTK inhibitors can sensitize BL cells to apoptosis [169].

The B-cell surface marker CD20 is the primary target for the treatment of BL. Several anti-CD20 monoclonal antibodies have been developed to treat B-cell malignancies, and the FDA has approved Rituximab for this purpose [170–172]. Several mechanisms have been proposed for anti-CD20 monoclonal antibody-mediated suppression of B-cell malignancies, including direct induction of apoptosis [171]. It was shown that Rituximab induces apoptotic cell death in a caspase-dependent manner via the p38 kinase pathway [173]. p38 signalling pathway is known to induce apoptotic cells through the induction of PUMA. Further, it was shown that activation of BCL-XL prevents Rituximab-mediated apoptotic cell death, indicating that PUMA might play a critical role in caspase activation. In addition, Rituximab is always used with a combination of different chemotherapeutic agents like cyclophosphamide, vincristine, doxorubicin, ifosfamide, etoposide, cytarabine and methotrexate. All these chemotherapeutic drugs help to induce apoptotic cell death. Therefore, PUMA might play a vital role in the induction of apoptotic cell death during chemoimmunotherapy treatment. Recently, in vitro and mice studies showed that β-elemene, a natural product from the Chinese herb Curcuma wenyujin, effectively inhibited the growth and induced the apoptosis of BL cells through upregulation of PUMA expression and activating PUMA-related apoptotic signalling pathway [174].

Chronic lymphocytic leukemia (CLL)

Chemotherapeutic agents like cyclophosphamide and fludarabine induce PUMA-mediated apoptosis, highlighting its role in enhancing chemosensitivity [175–177]. In CLL, cyclophosphamide-treated cells displayed p53-mediated activation of PUMA along with NOXA and BIM leading to apoptotic cell death [176]. Another drug, Fludarabine is a purine analogue which activates p53 and induces apoptosis in CLL cells. Further detailed studies showed that p53-mediated upregulation of PUMA plays a major role in chemosensitivity to fludarabine and NOXA and BIM play a restricted role [177]. Zhu et al. found that PUMA expression is significantly upregulated in CLL cells upon fludarabine treatment without alteration of NOXA and BIM expression [178]. They showed that NOXA or BIM is dispensable for PUMA-mediated apoptosis induction of CLL cells but dependent on p53 upon fludarabine treatment.

Multiple myeloma

Multiple myeloma (MM) is a cancer of plasma cells. They produce abnormal antibodies. Several genes such as cyclin D1, Myc, TP53, RB1, and RAS are deregulated in MM. It is reported that miR-221/222 is highly expressed in MM samples and promotes MM progression. Their study demonstrated that miR-221/miR-222 attenuates the expression of many pro-apoptotic proteins including PUMA [179].

Chemotherapeutic drugs like dexamethasone, bortezomib, carfilzomib and lenalidomide are routinely used to treat MM patients. Most of these drugs are known to inhibit MM progression through PUMA-mediated apoptotic cell death of MM cells. It was shown that 84% of MM patients respond to dexamethasone treatment along with vincristine and doxorubicin [180]. Another study demonstrated that bortezomib along with 5-azacytidine and doxorubicin facilitate apoptotic cell death of MM cells through the induction of several pro-apoptotic proteins including PUMA [181]. Similarly, bortezomib along with hypoxia-activated prodrug TH-302 induce PUMA and NOXA to promote apoptotic cell death of MM cells [182].

Solid tumors

Glioblastoma (GBM)

PUMA is silenced epigenetically in GBM [183]. Restoring its expression with epigenetic drugs, BET inhibitors [184], or gene therapy enhances sensitivity to treatments like temozolomide, overcoming resistance [185].

Esophageal cancers

Platinum-based drugs and anti-angiogenic therapies induce PUMA-mediated apoptosis. Oxaliplatin and capecitabine are the first-line chemotherapeutic drugs for esophageal cancer (EC) [186]. Both these drugs are known to induce apoptotic cell death. Both these drugs induce DNA damage in cancer cells. However, the molecular mechanism of cell death by these drugs is not known for EC. We speculate that oxaliplatin and capecitabine might be inducing cell death through PUMA-mediated induction of apoptosis to prevent EC progression as treatment of these drugs is known to activate PUMA. Nivolumab in combination with chemotherapy increases treatment efficacy by targeting PUMA-related pathways [187, 188].

Melanoma

Melanoma is a disease of cancer cells originating from melanocytes and is the 5th most common cancer in USA. Eighty per cent of skin cancer deaths are due to melanoma [189]. It was observed that BRAF is frequently mutated (BRAFV600E) in melanoma to constitutively activate the MAPK kinase pathway [190]. It was shown that BRAF silences several genes to promote melanoma [191]. Like other cancers, PUMA also plays a critical role in the suppression of melanoma. It was shown that clinically approved BRAF inhibitor PLX4032 induces apoptosis of melanoma cells bearing BRAFV600E mutation through induction of PUMA [192]. Further, it was shown that prolonged treatment of PLX4032 results in acquired drug resistance. Mechanistically, it was shown that activation of the receptor tyrosine kinase cMET-mediated downregulation of PUMA is responsible for drug resistance. Similarly, it is reported that inhibition of MEK results in apoptotic melanoma cell death of melanoma cells through induction of PUMA level as well as reduction of MCL-1 [193]. Furthermore, it was observed that inhibition of p38 MAPK also increases apoptotic cell death of melanoma cells through induction of PUMA. Interestingly, it was shown that p38 inhibition-mediated activation of caspase cleaves PUMA to induce PUMA-dependent apoptotic cell death [194]. Another study demonstrated that chloroquine stabilizes PUMA to induce apoptotic cell death of melanoma xenograft in mice through the lysosome-independent activity of chloroquine [195]. Another study reported that exogenously expressed E2F1 sensitises melanoma cells to apoptotic cell death by activating PUMA [29]. These studies reveal that PUMA activation plays a critical role in inhibiting melanoma progression.

Pancreatic cancer

PUMA sensitizes tumors to chemotherapy (gemcitabine, 5-FU) by promoting apoptosis [196]. Natural compounds like apigenin [197, 198] and rottlerin [199] also upregulate PUMA, offering potential complementary therapies.

Prostate and ovarian cancers

PUMA is a critical regulator of apoptotic cell death, making it a promising therapeutic target in prostate and ovarian cancers. In prostate cancer, androgen receptor (AR) suppresses PUMA expression, impairing apoptosis [200–202]. AR inhibitors like abiraterone [200] and phenyl butyl isoselenocyanate (ISC-4) [203] induce apoptosis by restoring PUMA levels. Similarly, estrogen receptor β (ERβ) enhances FOXO3a-mediated PUMA activation, offering an alternative therapeutic strategy [204]. Epigenetic regulators like SOX4 [205] and miR-125b [51] also downregulate PUMA, while agents like curcumin [206], resveratrol [207], and MDM2 inhibitors [208, 209] restore its expression to sensitize cancer cells to treatments such as docetaxel and radiation.

In ovarian cancer, PUMA enhances chemosensitivity to drugs like cisplatin, etoposide, and methotrexate by downregulating anti-apoptotic proteins (e.g., BCL-XL, MCL-1) [210, 211]. Natural compounds like diallyl trisulfide [212] and trametinib [213] increase PUMA expression, inducing apoptosis even in chemoresistant cells.

Overall, therapeutic strategies targeting PUMA, whether through direct activation or inhibition of its repressors, hold the potential to enhance treatment efficacy, overcome resistance, and mitigate side effects in prostate and ovarian cancers.

Clinical implications

PUMA is a key mediator of apoptotic cell death and a promising therapeutic target. Its role as a chemosensitizer and radiosensitizer makes it central to advancing combinatorial cancer therapies. Therapeutic strategies aimed at restoring or enhancing PUMA expression could improve outcomes across diverse cancer types, particularly in resistant and aggressive tumor. Targeting PUMA-related pathways offers a promising avenue for cancer treatment. Efforts to overcome resistance mechanisms and develop therapies that modulate PUMA expression or activity can improve outcomes for patients across various malignancies (Table 1).

Table 1 Therapeutic agents inducing apoptosis via PUMA-mediated pathway

Sl No	Cancer type	Drug/Compound Name	Role	References
1	Acute myeloid leukemia	CI-1040 (MEK inhibitor)	Induces apoptosis by upregulating PUMA in both mRNA and protein levels.	[95]
		AZD6244 (MEK inhibitor) + Nutlin-3a (MDM2 antagonist)	The combination of these two drugs synergistically induces proapoptotic responses in AML cell lines.	[96]
		Azacitidine or decitabine (hypomethylating agent)	Dephosphorylate FOXO3a which leads to translocation from the cytoplasm to the nucleus and targets PUMA expression which facilitates apoptosis.	[99]
2	Breast Cancer	Tamoxifen (anti-estrogen)	Promotes PUMA-mediated apoptotic cell death in estrogen receptor (ER) positive breast cancer.	[73]
		Toremifene (anti-estrogen)	Induces apoptosis of ER-positive breast cancer cells but the clear mechanism is not known.	[102]
		Neratinib (HER2 inhibitor)	HER2 inhibitor-mediated suppression of HER2-overexpressed breast cancer malignancy is critically dependent on the presence of PUMA and BIM expression.	[103, 104]
		BEZ235 or AZD8055 (mTOR inhibitor) + BH3 mimetics	The combination of these drugs facilitates the degradation of MCL-1 and promotes PUMA release of proapoptotic proteins like BIM, BAK and BAX to increase apoptosis in TNBC.	[105]
		Curcumol	Induces apoptosis through induction of PUMA in a p73-dependent manner.	[107]
		Doxorubicin and Cyclophosphamide	Induces PUMA levels to promote apoptosis.	[115]
		MY11 (a chalcone derivative)	Induces apoptosis by activating NF-κB/PUMA/mitochondrial apoptosis pathway.	[117]
		Goniothalamin (a styryl-lactone)	Induces apoptosis by upregulating the expression of PUMA along with other apoptosis-related proteins, including NOXA, BAX, and BIM.	[118]
		Goniothalamin + cyclophosphamide/5-fluorouracil/paclitaxel/vinblastine	Synergistically induces PUMA-mediated apoptotic cell death.	[118]
3	Burkitt’s lymphoma	5-Aza (hypomethylating agent)	Treatment of BL cells with 5-Aza sensitizes the apoptosis induction by inducing PUMA expression.	[154]
		MS1943 (a selective EZH2 degrader) and Ibrutinib (BTK inhibitor)	The combination of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated PUMA, BAX, cleaved PARP, and cleaved caspase-3 thereby inducing apoptosis.	[156]
		Rituximab	Induces apoptotic cell death in a caspase-dependent manner via the p38 kinase pathway. p38 is known to induce apoptosis through the induction of PUMA.	[160]
		β-elemene (a natural product from the Chinese herb Curcuma wenyujin)	Induces the apoptosis of BL cells through upregulation of PUMA expression.	[161]
4	Chronic lymphocytic leukemia	Cyclophosphamide	Cyclophosphamide induces p53-mediated activation of PUMA along with NOXA and BIM leading to apoptotic cell death.	[163]
		Fludarabine (a purine analogue)	p53-mediated upregulation of PUMA plays a major role in chemosensitivity to fludarabine.	[164]
5	Colon Cancer	Adriamycin	Induces apoptotic cell death through the induction of PUMA in a p53-dependent manner.	[127]
		17-AAG (Hsp90 inhibitor)	Induce p53-dependent PUMA induction in CRC cells.	[134]
		Taurine	Induces apoptosis in human colon carcinoma cells through induction of PUMA in a p53-dependent manner.	[135]
		Tazemetostat (EPZ-6438) (inhibitor of EZH2)	Shows its anti-colorectal cancer activity in a PUMA activation-dependent manner.	[133]
		UCN-01 (multi-kinase inhibitor - inhibits CDK, CHK1, PKC, AKT and PDK1)	Induces apoptosis in PUMA dependent manner.	[136]
		Crizotinib (c-MET/ALK inhibitor) the multikinase inhibitor drug sunitinib	Induce PUMA-mediated cell death in colon cancer.	[137, 138]
		Sorafenib (a multi-kinase inhibitor)	Sorafenib in colon cancer cells increases glycogen synthase kinase 3β (GSK3β) and ERK activation to increase the level of PUMA and induce apoptosis.	[139]
		ZM-447439 and VX-680 (aurora kinase inhibitor)	Function through different transcription factors, such as p73, to up-regulate levels of PUMA and other Bcl-2 family members to induce apoptosis.	[140]
		Gilteritinib (FMS-like tyrosine kinase 3 inhibitor) alone or in combination with 5-FU/Cisplatin	Suppresses CRC through PUMA-induced mitochondria-mediated apoptosis in a p53-independent manner.	[141, 142]
		Cabozantinib in combination with Cetuximab and 5-FU	Synergistically induces PUMA-dependent apoptosis in CRC cells.	[143]
		Idelalisib (a potent inhibitor of p110δ isoform of PI3K)	Enhances the expression of PUMA through GSK-3β/NF-κB pathway to induce apoptotic death of CRC cells.	[144]
		Osimertinib (irreversible EGFR/HER2 tyrosine kinase inhibitor)	Osimertinib treatment mediated increased PUMA expression in CRC cells is controlled by p73 through PI3K/AKT pathway inhibition.	[145, 146]
		Copanlisib (inhibitor of PI3K that preferentially inhibits PI3Kδ and PI3Kα)	Prevents the growth of CRC cells by inducing PUMA-mediated apoptosis in a p53-independent but FOXO3a-dependent manner.	[147]
6	Lung cancer	Gefitinib (an EGFR inhibitor)	Induce apoptotic cell death of NSCLC cells in a PUMA activation-dependent manner.	[152]
		Aurora kinase inhibitor + Gefitinib	Aurora B inhibition leads to inhibition of phosphorylation at Ser87 phosphorylation of BIM that stabilizes BIM. BIM is then responsible for the transactivation of PUMA. to induce apoptotic cell death through FOXO1/3.	[153]
		Propofol (inhibitor of the ERK1/2)	Induce p53-dependent PUMA-mediated apoptosis.	[154]
		Metformin + Buparlisib (pan-PI3K inhibitor)	Metformin enhances the apoptotic cell death activity of pan-PI3K inhibitor buparlisib through upregulated PUMA in NSCLC cells.	[158]
		Afatinib (a tyrosine kinase inhibitor)	Induces apoptotic cells of NSCLC through inactivation of AKT.	[157]
		Bevacizumab (mAb against VEGF)	Inhibits cancer cell proliferation by increasing the expression of CHOP. CHOP induces apoptosis through the activation of PUMA.	[156]
		Deguelin (a rotenoid extracted from the African plant Mundulea sericea)	Activate PUMA in a p53-dependent manner to induce apoptotic cell death in lung cancer cells through the inactivation of the PI3K/AKT pathway.	[159]
		Genistein	Induces apoptotic cell death of multiple lung cancer cells through activation of PUMA in a dependent manner.	[160]
		Xanthohumol (a naturally occurring active ingredient of Chinese medicine Hops)	Induce PUMA-dependent apoptotic cell death of lung cancer cells in vitro as well as in vivo through inactivation of the AKT pathway.	[161]
		AdPUMA + adriamycin/etoposide/cisplatin/γ-irradiation	The introduction of PUMA could be an effective strategy to sensitize lung cancer cells against these drugs.	[162]
7	Melanoma	PLX4032 (BRAF inhibitor)	Induces apoptosis of melanoma cells bearing BRAFV600E mutation through induction of PUMA.	[186]
		U0126 (MEK inhibitor)	Results in apoptotic cell death of melanoma cells through induction of PUMA level as well as reduction of MCL-1.	[189]
		MEK inhibitor + ABT-737 (BH3 mimetic)	Synergistically induces PUMA-dependent apoptotic cell death in melanoma cell lines.	[190]
8	Multiple myeloma	Dexamethasone, bortezomib, carfilzomib and lenalidomide	Most of these drugs are known to induce apoptotic cell death of multiple myeloma cells through the induction of PUMA.	[180]
		Bortezomib along with 5-azacytidine and doxorubicin	Facilitate apoptotic cell death of multiple myeloma cells through the induction of several pro-apoptotic proteins including PUMA.	[181]
		Bortezomib along with hypoxia-activated prodrug TH-302	Induce PUMA and NOXA to promote apoptotic cell death of multiple myeloma cells.	[182]

Conclusion and future perspectives

PUMA is a key player in the apoptotic response to a variety of stimuli. Initially identified as a direct transcriptional target of the tumor suppressor protein p53, PUMA mediates apoptotic cell death upon activation [6, 7]. Early studies suggested that PUMA activation was solely driven by p53’s transcriptional regulation. However, subsequent research has revealed a more complex regulatory landscape, with additional transcription factors involved in PUMA expression. Furthermore, it has become clear that PUMA’s activity is regulated at multiple levels: transcriptionally, post-transcriptionally through interactions with miRNAs and long non-coding RNAs, and post-translationally by kinases and ubiquitin ligases.

Despite significant advances in understanding PUMA’s role in cell death, several key questions remain unanswered. Addressing these gaps will deepen our knowledge of the intricate regulatory network that regulates PUMA and its implications for cancer biology and therapy. One promising area for future investigation is the identification and characterization of post-translational modifiers of PUMA. Kinases, phosphatases, and ubiquitin ligases may regulate PUMA’s stability, localization, and interactions with other cellular proteins, thereby influencing its function in cell death pathways. By understanding how these modifiers impact PUMA activity, we could uncover new therapeutic strategies. For instance, enhancing PUMA’s activity in cancer cells could promote apoptosis, potentially overcoming resistance to chemotherapy.

Another critical avenue of research is exploring the interplay between PUMA and various forms of cell death. While PUMA’s role in apoptosis is well-documented, its involvement in necroptosis, autophagic cell death, and ferroptosis is less understood. Investigating how PUMA interacts with proteins such as Beclin 1 and how its regulation changes under specific stress conditions, such as UV or γ-radiation, will provide valuable insights into its multifaceted role in cell death. Furthermore, identifying factors that limit PUMA activity in certain contexts could reveal how cells evade death, offering potential strategies to selectively sensitize cancer cells to treatment.

One promising therapeutic approach involves adenovirus-mediated delivery of PUMA (Ad-PUMA), which has shown potential in sensitizing cancer cells to chemotherapy. By directly enhancing PUMA expression in tumor cells, Ad-PUMA could help overcome resistance mechanisms and increase the effectiveness of apoptosis-inducing therapies. Although Ad-PUMA presents a promising approach to sensitize cancer cells to chemotherapy, it lacks sustained expression. Therefore, adenoviral expression faces challenges for long-term clinical use. However, future studies could explore strategies to overcome this limitation, such as the development of more efficient and stable delivery systems.

Lastly, understanding the broader implications of PUMA regulation for tumor progression and treatment resistance is essential. By combining insights from transcriptional, post-transcriptional, and post-translational regulation of PUMA with high-throughput technologies like CRISPR screens and proteomics, we may uncover new drug targets and biomarkers. These discoveries could form the basis for developing novel therapeutic strategies aimed at harnessing PUMA activation to improve cancer cell sensitivity to existing treatments. By addressing these future research directions, we can further unravel the complex regulatory mechanisms governing PUMA and develop targeted therapies for cancer and other diseases associated with dysregulated cell death.

Abbreviations

Ad-PUMA

Adenovirus-mediated delivery of PUMA

ALK

Anaplastic lymphoma kinase

AML

Acute myeloid leukemia

AP

Acetaminophen

AR

Androgen receptor

BBC3

Bcl-2-binding component 3

Bcl-2

B-cell lymphoma 2

BH

Bcl-2 homology

BL

Burkitt’s lymphoma

CHOP

C/EBP homologous protein

CLL

Chronic lymphocytic leukemia

CMA

Chaperone-mediated autophagy

CRC

Colorectal cancer

DAMP

Damage-associated molecular pattern

EBV

Epstein–Barr virus

EC

Esophageal cancer

EGFR

Epidermal growth factor receptor

EZH2

Enhancer of zeste homolog 2

FOXO3a

Forkhead box protein O3a

GSK-3

Glycogen synthase kinase

GTN

Goniothalamin

MLS

Mitochondrial localization signal

MLKL

Mixed-lineage kinase domain-like protein

MM

Multiple myeloma

NSCLC

Non-small cell lung cancer

PRC2

Polycomb repressive complex 2

PUMA

p53 upregulated modulator of apoptosis

RIP3

Receptor-interacting protein 3

TNBC

Triple-negative breast cancer

VEGF

Vascular endothelial growth factor

Author contributions

S.S.T., T.S., G.K.B., and M.K.S. discussed and finalized the content of the review. S.S.T., T.S., and M.K.S. conducted the literature survey. S.S.T., T.S., K.M., N.B.G., G.K.B., R.N.G., and M.K.S. actively contributed to writing the manuscript. S.S.T., K.M., and M.K.S. conducted thorough editing, and M.K.S. supervised the entire manuscript. K.M. prepared the table, organized the references, formatted the manuscript, and created all figures and the graphical abstract using a Biorender paid subscription.

Funding

This work is supported by intramural financial support from the National Centre for Cell Science, Department of Biotechnology, Ministry of Science and Technology, Government of India.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

There is no conflict of interest to declare.