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. 2026 Feb 5;11(6):8897–8910. doi: 10.1021/acsomega.5c10194

The Role of PDE3A in Cancer

Shengyu Pu †, Qihe Zhang ‡, Mi Miao ‡, Bohong Chen ‡, Jiarui Xu ‡, Jingyi Lei ‡, Xiaojiang Tang §, Na Hao §,*
PMCID: PMC12917846  PMID: 41726589

Abstract

Objective: PDE3A is a key member of the cyclic nucleotide phosphodiesterase family. By modulating intracellular cAMP and cGMP levels, it participates in diverse physiological processes such as platelet activation, cardiac function, oocyte maturation, and vascular smooth muscle cell proliferation. Recent studies have revealed that PDE3A also plays critical roles in multiple malignant tumors. This study aims to investigate the regulation of PDE3A expression, its role in cancer, and its potential as a therapeutic target, with a particular focus on its impact on tumor cell proliferation, metastasis, and resistance to chemotherapy. Methods: A systematic review of 221 PubMed-indexed articles published through April 2, 2025, was conducted to examine the expression and functional mechanisms of PDE3A in various cancer types. This study explored the regulation of PDE3A expression in cancer cells, its role in cell signal transduction, and its involvement in tumor initiation, progression, metastasis, and chemotherapy resistance. Additionally, it explored the inhibition of PDE3A and its potential as a therapeutic target for cancer treatment. Results: PDE3A is aberrantly overexpressed in various cancers, particularly in gastrointestinal stromal tumors, hepatocellular carcinoma, and breast cancer. Its expression is regulated at multiple levels, including DNA mutations (e.g., Y497C), DNA methylation, transcription factors (SFPQ, MYBL2), epigenetic modifications (such as FSCN1-mediated alternative splicing, m6A modification by METTL3, microRNAs targeting PDE3A), and post-translational modification (14–3–3 protein). PDE3A contributes to cancer stem cell characteristics, metastasis, and chemotherapy resistance through both cAMP/PKA-dependent and cAMP/PKA-independent pathways, including the NF-κB, YAP/TEAD, and β-catenin/ID3 signaling axes. Notably, PDE3A can form a molecular gel-dependent complex with SLFN12 to induce apoptosis, a mechanism targeted by novel drugs such as OPB-171775 and BAY 2666605. Furthermore, combining PDE3A inhibitors (e.g., cilostazol) with existing chemotherapy agents (e.g., imatinib) significantly enhances antitumor efficacy, particularly in refractory tumors like gastrointestinal stromal tumors, demonstrating a strong synergistic effect. Conclusion: PDE3A plays a pivotal role in tumorigenesis and cancer progression, with aberrant expression strongly associated with tumor proliferation, metastasis, and resistance to chemotherapy. As a therapeutic target, PDE3A holds significant potential. The development of PDE3A inhibitors or molecular adhesive agents may offer novel treatment strategies, particularly for chemotherapy-resistant tumor types.

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1. Introduction

PDE3 is a cytosolic enzyme that can hydrolyze cAMP and cGMP. It is usually classified into two subtypes (PDE3A and PDE3B). , A pivotal study conducted in 1992 reported the complete cDNA sequence of PDE3A, and numerous follow-up researches have demonstrated that PDE3A exists in at least three isoform variants within cellular environments. These isoforms share an identical C-terminal phosphodiesterase domain while differing significantly in their N-terminal regulatory regions. Biochemical analyses indicate that PDE3A exhibits a stronger binding affinity for cGMP compared to cAMP; however, its maximum reaction rate (Vmax) toward cAMP is approximately ten times higher than that toward cGMP. , This characteristic provides a mechanistic explanation for why cGMP can effectively impede the PDE3A-catalyzed hydrolysis of cAMP. Experiments utilizing truncated PDE3A mutants confirmed that the C-terminal domain of PDE3A alone is competent enough to catalyze the hydrolysis of cAMP and cGMP.

PDE3A is mainly found in tissues such as platelets, heart, and vascular smooth muscle, and can control the concentrations of the two cyclic nucleotides by hydrolyzing them. , cAMP and cGMP, as second messengers, can participate in signal transduction in platelet activation, excitation-contraction coupling in the heart, and growth of vascular smooth muscle, thereby exerting their functions. It has been well established that PDE3A modulates intracellular concentrations of cAMP and cGMP, thereby regulating a series of vital biological processes including oocyte maturation, muscle contraction, and vascular dilation. , Pharmacological inhibition of PDE3A’s phosphodiesterase activity has been shown to exert multiple biological effects: it can interfere with oocyte maturation, reduce platelet production, and elevate the risk of sudden cardiac death in patients suffering from heart diseases. Next, we will discuss the physiological and pathololgical functions of PDE3A in detail.

2. PDE3A in Normal Tissue

2.1. PDE3A and Cardiac Function

Research found that PDE3A regulates the autonomous rhythm and myocardial contractile function of cardiac pacemaker cells. In these cells, PDE3A works synergistically with PDE4 to maintain basal cAMP levels and regulate the spontaneous beating frequency. Dual inhibition of PDE3A and PDE4 can significantly elevate cAMP concentrations, enhance L-type calcium current (I(Ca,L)), and promote local Ca2+ release (LCRs), thereby accelerating diastolic depolarization (DD) and increasing heart rate. This synergistic effect has been demonstrated in the sinoatrial node of various species, including rabbits and mice. Regarding myocardial contractile function, PDE3A knockout (KO) mice exhibit a significantly elevated basal heart rate, while PDE3B KO mice show no difference compared to wild-type animals. The absence of a heart rate response to the PDE3 inhibitor cilostamide in PDE3A KO mice further suggests that PDE3A is the predominant PDE3 isoform in the heart, responsible for regulating basal heart rate. Additionally, the cAMP-PDE activity in membrane preparations from the hearts of PDE3A KO mice is reduced and not inhibited by cilostamide, further supporting the dominant role of PDE3A in myocardial cAMP metabolism.

2.2. PDE3A and Platelets

PDE3A plays a crucial role in platelet activation. Studies have shown that PDE3A hydrolyzes cAMP to 5′-AMP, maintaining low cAMP levels within platelets and thereby lowering the threshold for activation. In atherosclerotic conditions, oxidized low-density lipoprotein (oxLDL) activates the Src/Syk/PKC signaling pathway through the CD36 receptor, leading to sustained activation of PDE3A. Thrombin also activates PKC via protease-activated receptors (PARs), which phosphorylate multiple serine residues, including Ser298, on PDE3A, thereby enhancing its catalytic activity. These mechanisms collectively reduce cAMP levels, diminishing the inhibitory effect of prostacyclin (PGI2) and promoting excessive platelet activation. In PDE3A KO mice, basal cAMP levels in platelets are significantly elevated, rendering them insensitive to PDE3 inhibitors, and they exhibit a marked antithrombotic effect in a pulmonary thrombosis model. In contrast, PDE3B deficiency does not produce this phenotype. These findings underscore the central role of PDE3A in regulating platelet function, highlighting it as a potential target for antiplatelet therapy.

2.3. PDE3A and Oocytes

PDE3A regulates the activation and dormancy of primordial follicles. In the ovaries of neonatal mice, the coordinated upregulation of PDE3A and ADCY3 maintains stable cAMP concentrations, providing a molecular basis for the homeostasis of primordial follicles. Inhibition of PDE3A effectively increases cAMP levels in oocytes, significantly accelerating the activation of primordial follicles. Further studies have demonstrated that elevated cAMP levels activate mTORC1 and PI3K signaling through PKA, leading to phosphorylation of the downstream factor rpS6 and the phosphorylation and translocation of the transcription factor FOXO3a from the nucleus to the cytoplasm (CL-FOXO3a), thereby driving follicular activation. This regulatory balance is essential for maintaining the reproductive lifespan and health of females.

2.4. PDE3A in Pathology Diseases

2.4.1. PDE3A and Arrhythmias

The study conducted by Alessandra Ghigo et al. highlighted that PDE3A dysfunction is a key mechanism underlying catecholamine-sensitive arrhythmias. In the PI3Kγ-deficient (PI3Kγ–/–) mouse model, PDE3A activity is significantly reduced, leading to delayed cAMP clearance following β2-adrenergic receptor (β2-AR) activation. This delay results in excessive phosphorylation of PKA-mediated L-type calcium channels (Cav1.2) and phospholamban, ultimately triggering spontaneous calcium release events and ventricular arrhythmias. Further investigation revealed that PI3Kγ forms a complex with PDE3A via its scaffold function, activating PDE3A through PKA-mediated signaling. This interaction limits local cAMP accumulation, thereby preventing calcium-dependent arrhythmias. Consequently, PDE3A serves as a crucial effector molecule in the PI3Kγ-mediated antiarrhythmia signaling pathway. PI3Kγ couples PKA with PDE3A, precisely compartmentalizing and negatively regulating the β2-AR/cAMP signal. Disruption of this mechanism represents a key molecular basis for the development of arrhythmias.

2.4.2. PDE3A and Chronic Heart Failure

A 2023 study revealed that the interaction between PDE3A and SERCA2 is implicated in chronic heart failure (CHF). In this condition, impaired myocardial contraction is directly associated with reduced activity of the sarcoplasmic reticulum calcium pump (SERCA2). PDE3A binds directly to SERCA2 and inhibits its function. Functional studies have demonstrated that disrupting this interaction with a specific peptide, such as OptF, significantly enhances SERCA2 activity and improves calcium handling in myocardial cells. These findings suggest that targeting the PDE3A-SERCA2 interaction may offer a novel therapeutic strategy for CHF.

2.4.3. PDE3A and Female Infertility

PDE3A is implicated in female infertility. Studies have shown that deficiency of the PDE3A gene (PDE3A–/–) results in complete infertility in female mice. The absence of PDE3A leads to elevated cAMP levels in oocytes and continuous activation of PKA. Activated PKA phosphorylates downstream targets, such as Cdc25B and PlK1, which inhibit the activation of the maturation-promoting factor (MPF). This disruption causes meiotic division of oocytes to arrest at the germinal vesicle (GV) stage, preventing further maturation and completion of fertilization. , In vitro studies have shown that inhibition of PKA can effectively alleviate meiotic arrest and restore fertilization capacity. These findings suggest that PDE3A could serve as a potential target for intervention in female contraception or assisted reproductive technologies.

Beyond these well-documented regulatory roles of PDE3A that are mediated by classic second messengers, a growing body of research has uncovered cAMP- and cGMP-independent functions of PDE3A in facilitating cancer cell apoptosis in recent years (Figure ). Several PDE3 enzyme inhibitors have been shown to exert cytotoxic effects on cancer cells. This review examined the expression and regulation of PDE3A in cancer cells, its role in cell signal transduction, and its involvement in tumor initiation, progression, metastasis, and chemotherapy resistance. Additionally, the study explored the inhibition of PDE3A and its potential as a therapeutic target for cancer treatment.

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Summary of the physiological or pathological roles of PDE3A in various tumors or tissues.

3. Methods

3.1. Search Strategy

All the studies mentioning PDE3A and its association with cancer were retrieved from PubMed. The advanced search terms we used were: ((PDE3A) OR (phosphodiesterase 3A)) AND ((tumor) OR (cancer)). As of April 2, 2025, our search results yielded 221 papers.

3.2. Screening Criteria

These articles are classified into the following categories: 10 articles related to breast cancer, among which 2 are highly relevant; 2 articles related to bladder cancer, but not related to PDE3A; 4 articles related to cervical cancer, among which 3 are highly relevant; 1 article related to glioma, but related to NPP1; 3 articles related to lymphoma, with little relevance; 1 article related to mucinous lipoma; 2 articles related to esophageal cancer, with 1 being highly relevant; 3 articles related to prostate cancer, all without relevance; 5 articles related to bone tumors, with only 1 being highly relevant; 5 articles related to ovarian cancer, with 1 being highly relevant; 8 articles related to kidney cancer, with little relevance; 5 articles related to thyroid, with 1 being highly relevant; 9 articles related to pancreatic cancer, with 1 discussing pancreatic ductal carcinoma; 14 articles related to colorectal cancer, mainly related to PDE3B; 7 articles related to melanoma, with only 1 being relevant; 28 articles related to lung cancer, with only 2 being relevant; 9 articles related to gastric cancer, all irrelevant; 17 articles related to gastrointestinal stromal tumors (GIST), with 7 having significant relevance; 27 articles related to liver cancer, with 2 being highly relevant; 27 articles related to vascular tumors, with only 1 being relevant; 1 article related to gum cancer; 1 article related to hematological tumors.

4. Results and Discussion

4.1. The Expression of PDE3A in Cancer

PDE3A expression is dysregulated in a spectrum of human cancers, with notable enrichment in GIST, hepatocellular carcinoma (HCC), gingival squamous cell carcinoma, breast cancer, human squamous carcinoma, ovarian carcinoma, myxoid liposarcoma, and certain subtypes of colorectal cancer. PDE3A has been most extensively studied in GIST. Immunohistochemical analysis of tissue microarrays has demonstrated PDE3A immunoreactivity in 92% of KIT-positive tumors, including both spindle and epithelioid subtypes as well as metastatic lesions. This high expression is lineage-specific, as GIST originates from interstitial cells of Cajal (ICC), where PDE3A is constitutively expressed throughout development and plays a role in ICC maturation. In PDE3A-deficient mice, ICC density is halved, underscoring the protein’s essential role in the development of this cell lineage and its derivative tumors.

Compared with nonalcoholic steatohepatitis (NASH) and normal liver tissue, PDE3A is one of the proteins upregulated in alcoholic hepatitis (AH). Since AH progresses to cirrhosis and HCC at a higher rate than NASH, PDE3A overexpression may contribute to the increased tumorigenic potential of AH-associated liver disease. Similarly, in human gingival carcinoma, PDE3A expression is significantly elevated in tumor tissues compared to normal gingiva, and higher enzyme activity is observed in cases with lymph node metastasis, suggesting a correlation between PDE3A levels and disease progression. Notably, PDE3A expression is not universal across all cancer types. In colorectal cancer cell lines such as HT-29 and DLD-1, PDE3A mRNA is undetectable, indicating tissue-specific regulation of its expression. ,

Studies have found that high expression of PDE3A in lung adenocarcinoma (LUAD) is associated with better patient prognosis. Overexpression of PDE3A can make A549/Cis cells more sensitive to cisplatin and enhance cisplatin-induced caspase-3 activation (a marker of apoptosis), although overexpression of PDE3A alone does not induce cell apoptosis. Additionally, high PDE3A expression is correlated with favorable overall survival (OS, HR = 0.53, p < 0.0001) and progression-free survival (PFS, HR = 0.54, p < 0.001) in patients with LUAD (median OS: 136.33 vs 72 months; median PFS: 45.3 vs 19 months for high vs low expression). In contrast, high PDE3A expression was associated with poorer OS (HR = 1.56, p = 0.017) and PFS (HR = 1.83, p = 0.04) in patients with lung squamous cell carcinoma (LUSC).

PDE3A is also identified as a significantly mutated gene in esophageal small cell carcinoma (SCCE) and is upregulated in breast cancer, where it associates with poor prognosis, metastasis, and cancer stem cell (CSC) properties. In nonsmall cell lung cancer (NSCLC), PDE3A is downregulated via hypermethylation in cisplatin-resistant cells, with subtype-specific prognostic value (favorable in adenocarcinoma, unfavorable in squamous cell carcinoma). Squamous cell carcinoma (HeLa cells) shows selective overexpression of PDE3A and PDE2A, correlating with sensitivity to PDE inhibitors.

It was pointed out that the expression level of PDE3A in AML cells is higher than that in normal cells, and its high expression is associated with worse event-free survival (EFS) in newly diagnosed AML patients. It was found that the PDE3A inhibitor anagrelide (ANA) can significantly inhibit the proliferation of AML cells with high PDE3A expression, while having little effect on cells with low PDE3A expression. Moreover, ANA shows a synergistic effect with other chemotherapeutic drugs in AML cells with high PDE3A expression, especially the combination of ANA and idarubicin, which shows the most significant synergistic effect. This synergistic effect inhibits the survival of AML cells with high PDE3A expression through GSDME-mediated pyroptosis, which is initiated by caspase-3 activation triggering GSDME cleavage. In leukemia animal models with high PDE3A expression, the combination treatment of ANA and IDA significantly reduced leukemia burden and extended survival, indicating that this combination treatment is a promising therapeutic strategy for high-PDE3A expression AML patients.

Additionally, analysis revealed that both PDE3A and Schlafen family member 12 (SLFN12) are highly expressed in various cancers, particularly in myxoid liposarcoma (MLPS). SLFN12 is a protein with RNase activity. Recent studies have revealed that the interaction between PDE3A and SLFN12 plays a crucial role in tumorigenesis, development, and targeted therapy, emerging as a research hotspot in the field of cancer biology. Studies indicated that the coexpression of PDE3A and SLFN12 can serve as a biomarker for screening cancer patients sensitive to PDE3A modulators, offering a new therapeutic direction for MLPS and other tumor subtypes lacking effective precision treatment options.

4.2. The Regulation of PDE3A Expression in Cancer

4.2.1. DNA Mutation of PDE3A

A study conducted whole-exome sequencing on 50 DNA samples from healthy Korean individuals and identified five missense variants in PDE3A: D12N, Y497C, H504Q, C707R, and A980 V. Comparing the catalytic activity of the PDE3A missense variants with the wild-type revealed that all variant proteins had reduced catalytic activity (33–53%; p < 0.0001). Additionally, cilostazol exhibited a more pronounced inhibitory effect on PDE3A activity in the missense variants, particularly PDE3A Y497C. In summary, individuals carrying the PDE3A Y497C variant may have lower cAMP phosphodiesterase activity, which could lead to differences in cAMP-mediated physiological functions among individuals.

Another research presents a comprehensive genomic profiling of 55 SCCE patients via whole-exome sequencing, ultradeep targeted sequencing, and copy number microarray assays. The main results showed that eight significantly mutated genes were identified, including known drivers (TP53, RB1, NOTCH1, FAT1, FBXW7) and three novel esophageal cancer-related genes (PDE3A, PTPRM, CBLN2). Biallelic inactivation of TP53 and RB1, frequent MYC family (MYC, MYCL1) amplifications, and widespread alterations in the Wnt/β-catenin, cell cycle, and p53 pathways were observed. Notably, 96.4% of patients harbored Wnt pathway alterations, and NOTCH family mutations correlated with poorer OS. These findings uncover key molecular drivers of SCCE, challenge the current SCLC-mimetic treatment paradigm, and provide a foundation for developing precision therapies.

4.2.2. DNA Methylation of PDE3A

F-M Tian et al. investigates the role of PDE3A in cisplatin resistance of nonsmall cell lung cancer (NSCLC) and its association with patient survival found that PDE3A is hypermethylated in cisplatin resistant NSCLC and is a modulator of chemotherapy response. By reanalyzing GEO data set GDS5247 and mining TCGA database, researchers found that PDE3A is significantly downregulated in cisplatin-resistant NSCLC cells (e.g., H460/Cis and A549/Cis) compared to parental cells. This downregulation is attributed to DNA hypermethylation, as evidenced by a negative correlation between PDE3A expression and methylation levels in LUAD patients and restored PDE3A expression in A549/Cis cells treated with the demethylating agent 5-AZA-dC. These findings identify DNA hypermethylation-mediated PDE3A downregulation as a key mechanism of cisplatin resistance in NSCLC, particularly adenocarcinoma. PDE3A restoration enhances chemotherapy sensitivity, highlighting its potential as a therapeutic target. Additionally, PDE3A expression may serve as a subtype-specific prognostic biomarker for NSCLC, guiding personalized treatment strategies.

4.2.3. DNA Transcriptional Activation of PDE3A

Another article in 2017 revealed the role of SFPQ (a splicing factor rich in proline and glutamate) in PDE3A gene expression, filling the gap in the regulatory mechanism. In serum-induced PDE3A expression, it was found that the binding of SFPQ to the upstream regulatory region of PDE3A increased, indicating that SFPQ can regulate PDE3A mRNA levels as a transcriptional activator of PDE3A. PDE3A expression is reduced in cervical cancer cells. Overexpression of PDE3A can enhance the sensitivity of Hela cells to DNMDP, achieving an anticancer effect. Therefore, regulating PDE3A expression may effectively increase the sensitivity of cervical cancer to specific anticancer drugs, providing new ideas and directions for cancer treatment.

Another article studied the oncogenic role of MYBL2 in melanoma to determine whether it can serve as a diagnostic and therapeutic target for melanoma. MYBL2 often leads to poor prognosis and high proliferation and metastatic capabilities of cancer cells. Through RNA-Seq and ChIP-Seq analyses, PDE3A was identified as one of the downstream target genes of MYBL2. It was found that the expression of MYBL2 is positively correlated with the expression level of PDE3A, and high expression of PDE3A in melanoma patients is significantly associated with poor survival rates. This indicates that MYBL2 can transcriptionally activate PDE3A, regulating its expression and promoting the malignant progression of melanoma. Therefore, PDE3A can serve as a potential biomarker for assessing melanoma prognosis.

4.2.4. Epigenetic Modification of PDE3A mRNA

Recent research in NSCLC showed that FSCN1 (a RNA-binding protein) may regulate the expression of PDE3A by affecting the alternative splicing levels of mRNA precursors of NME4, NCOR2, and EEF1D, thereby controlling the proliferation, migration, and invasion of cancer cells. Silencing FSCN1 in A549 cells can significantly increased the expression level of PDE3A, which indicating that FSCN1 may inhibit the expression of PDE3A through some mechanism. Through RNA immunoprecipitation (RIP) and RNA-seq analysis, researchers found that FSCN1 can directly bind to the mRNA of PDE3A and may affect the expression of PDE3A by regulating the splicing level of its precursor mRNA. These findings revealed the potential mechanism of PDE3A in lung cancer progression and the interaction between FSCN1 and PDE3A, providing new perspectives and potential targets for molecular diagnosis and targeted therapy of lung cancer.

A recent study showed that in cervical cancer, METTL3 targets PDE3A through m6A modification and enhances the stability of PDE3A mRNA through YTHDF3, thereby promoting PDE3A protein expression, which in turn affects the proliferation and migration of cancer cells. The article suggests that the METTL3/YTHDF3/PDE3A axis could be a potential clinical target for cervical cancer treatment.

S. Yasmeen et al. investigated miRNAs targeting PDE3A as potential therapeutic targets for cerebral small vessel disease (CSVD), with a focus on cerebral microvascular endothelial dysfunction. Using in silico analysis (TargetScan, miRWalk), 67 PDE3A-targeting miRNAs were identified, with 49 expressed in the hCMEC/D3 human cerebral endothelial cell line. Coexpression meta-analysis clustered these miRNAs into seven groups, with the top two clusters (miR-221/miR-222 and miR-27a/miR-27b/miR-128) are linked to critical pathways in vascular integrity, immune regulation, and neurogenesis via KEGG analysis. Notably, hCMEC/D3 cells exclusively expressed PDE3A (not PDE3B). Transfection experiments confirmed that miR-27a-3p and miR-222–3p mimics significantly reduced PDE3A protein expression compared to control group. These miRNAs are known to be associated with CSVD risk factors (diabetes, hypertension), and can offer isoform-specific modulation of PDE3A, thereby avoiding side effects of nonselective PDE3 inhibitors like cilostazol. The findings highlight miR-27a-3p and miR-222–3p as promising therapeutic candidates for CSVD by targeting endothelial PDE3A to improve barrier function and cerebral blood flow.

4.2.5. Post-Translational Modifications of PDE3A Protein

Mercedes et al. found that PDE3A binds to 14–3–3 proteins in response to PMA-induced phosphorylation of Ser428. Researchers found that PDE3A coimmunoprecipitates with endogenous 14–3–3 proteins in a phosphorylation-dependent manner, with PMA (a PKC activator) inducing maximal binding. Inhibitor studies revealed PKC, not MAPK or SAPK2/p38, mediates this interaction. MS/MS and phosphospecific antibodies identified five in vivo phosphorylation sites on PDE3A, with Ser428 selectively phosphorylated by PMA and dephosphorylated by DNA replication inhibitors (aphidicolin, mimosine), correlating directly with 14–3–3 binding. Forskolin-induced PKA phosphorylation of Ser312 did not promote 14–3–3 binding, demonstrating 14–3–3′s ability to discriminate between phosphorylation sites. This study uncovers PKC-mediated Ser428 phosphorylation as the key trigger for PDE3A-14–3–3 interaction, highlighting multisite phosphorylation’s role in regulating PDE3A function and its potential involvement in cytoskeletal dynamics.

4.3. The Function of PDE3A in Cancer

Functionally, PDE3A contributes to oncogenesis through multiple mechanisms, involving both catalytic and noncatalytic mechanisms (Figure ). As a cyclic nucleotide hydrolase, PDE3A modulates intracellular cAMP levels to regulate cell proliferation, apoptosis, motility and so on. Beyond its enzymatic activity, a growing body of research is investigating the nonhydrolytic function of PDE3A, exerting noncatalytic oncogenic effects through protein–protein interactions, most notably with SLFN12. The PDE3A-SLFN12 complex, induced by small molecules such as DNMDP and OPB-171775, triggers SLFN12-mediated RNase activity, leading to selective cytotoxicity in cancer cells coexpressing both proteins, creating a unique dependency that can be exploited therapeutically. In addition, we have summarized all oncology studies of PDE3A and their related findings in Table , in order to provide a more comprehensive understanding of the role of PDE3A in the development and progression of various cancers, as well as its therapeutic potential. Next, we will describe the carcinogenic role of PDE3A in various tumors based on different phenotypes.

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Regulation of PDE3A expression and oncogenic phenotypes in various tumors.

1. A Collection of All Oncological Studies of PDE3A with Associated Findings .

Cancer Type of Study Experimental Environment Mechanism Mechanism Overview Reference
BC Gene expression analysis, functional studies in vitro and in vivo, computer-aided drug design, chemical synthesis, drug activity assessment Breast cancer cell lines, animal models, clinical data, computer simulations 1.Upregulation in human breast cancer tissues and the population of CSCs in highly metastatic variants of MDA-MB-231 and T-47D cancer cells. Upregulation Promoting proliferation and metastasis (CCDC88A) Hao et al. 2019
2.PDE3A induced the inflammatory nuclear factor NFkB signaling pathway by suppressing cAMP/PKA, which promotes the expression of the stem cell marker OCT4. PDE3A also promoted the translocation of CCDC88A from the cytoplasm to nuclei, thereby boosting the invasion–metastasis cascade in breast cancer. Therapy: PDE3A-selective inhibitor cilostazol and novel multifunctional pyridine compounds Malama et al. 2018
3.The PDE3A-selective inhibitor cilostazol and novel multifunctional pyridine compounds suppressed breast tumor growth and metastasis.    
CC Cell toxicity research, gene expression regulation mechanism and function research, and epigenetic regulation mechanism and function research in vitro Cervical cancer cell lines (Hela, SiHa, C33A), clinical tissue samples. 1. Significantly downregulation in cervical cancer tissues compared with adjacent normal tissues. Downregulation Cartledge et al. 2017
2. SFPQ-mediated upregulation of PDE3A expression markedly sensitized cervical cancer cells to anticancer agents, including DNMDP. Transcription factor (SFPQ) Rhee et al. 2017
3. METTL3 targets PDE3A via m6A modification and recruits YTHDF3 to facilitate the proliferation and metastasis of cervical cancer cells. Epigenetic modifications (m6A modification of METTL3) Liu et al. 2017
4. Pharmacological enhancement of the PDE3A-SLFN12 interaction by compounds such as zadafalin induced cell death in cervical cancer.    
MLPS Transcriptomics analysis, gene expression association study, in vitro drug sensitivity test Clinical fat sarcoma tissue samples, mucinous fat sarcoma cell lines 1. Upregulation in myxoid LPS, particularly in high-grade tumors. Upregulation Toivanen et al. 2023
2. Coexpression of PDE3A and SLFN12 in MLPS cells confers high sensitivity to PDE3A modulators, suggesting its potential as a target for precision therapy. Coexpression of PDE3A and SLFN12  
SCCE Genomic analysis, whole exome sequencing 55 clinical tissue samples of esophageal small cell carcinoma 1. One of the significantly mutated genes in Small cell carcinoma of the esophagus (SCCE) One of the significantly mutated genes Wang et al. 2018
OS Gene expression analysis, enzyme function study Normal osteoblasts (NHOst) and osteosarcoma cell line (SaOS-2) 1. Low activity of PDE3 in SaOS-2 cells Downregulation Ahlström et al. 2006
OC Structural biology research, drug development and optimization, first human clinical trials Crystal structure analysis of protein complexes, in vitro tumor cell models, patients with advanced solid tumors (Phase I clinical trial) 1. High expression in Ovarian Cancer. Upregulation Nazir et al. 2017
2. BAY 2666605, DNMDP and related compounds induce apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12), but former may cause thrombocytopenia in treated patients. Coexpression of PDE3A and SLFN12 Garvie et al. 2021 Papadopoulos et al. 2024 Chen et al. 2021
THCA Research on Gene Expression Regulation Chicken embryo villous allantoic membrane vascular system, human thyroid tissue 1. The PDE3A homologue is enriched in human thyroid tissue. Homologous enrichment Javerzat et al. 2009
2. PDE3A expression undergoes upregulation during vascular development in the chicken embryonic chorioallantoic membrane.
M Research on transcriptional regulatory mechanisms, bioinformatics analysis, and clinical correlation analysis Melanoma cell lines, clinical tumor tissue samples, public genomic databases (RNA-Seq and ChIP-Seq data) 1. High expression in melanoma. Upregulation Transcription factor (MYBL2) Zhong et al. 2022
2. Independent prognostic factor, risk factor.
3. MYBL2 drives melanoma proliferation and metastasis through the direct transcriptional activation of PDE3A.
LC Research on transcriptional regulatory mechanisms, analysis of RNA-protein interactions, multiomics integration analysis (transcriptome/proteome), study of chemotherapy resistance, research on the regulatory mechanisms of tumor microenvironment Nonsmall cell lung cancer cell lines (such as A549), EGFR-mutated lung cancer cell models, clinical tumor tissue samples, bioinformatics database (GEPIA2), RNA immunoprecipitation experimental system 1. In nonsmall cell lung cancer (NSCLC), the loss of FSCN1 and subsequent upregulation of PDE3A enhance cAMP hydrolysis, which suppresses proliferation and metastasis, promotes apoptosis, and is ultimately associated with improved patient survival and cisplatin sensitivity. Upregulation DNA methylation (NSCLC) Epigenetic modification (FSCN1-mediated alternative splicing) Promoting proliferation and metastasis Therapy: PDE3A inhibitor trequinsin Sun et al. 2023
2. In EGFR mutant lung cancer, ALDOA activates PDE3A via the β-catenin/ID2 axis to potentiate cancer cell invasion, metastasis, and M2 macrophage polarization, thereby accelerating tumor growth and immune evasion.The PDE3A inhibitor trequinsin reduces M2 macrophage polarization in EGFR mutant lung cancer cell lines and inhibits cell migration, invasion, and metastasis. Yeh et al. 2024
PDAC Research on the functions of cancer stem cells, research on combined drug therapy, and research on the mechanisms of signal pathways Pancreatic ductal adenocarcinoma cell model, animal xenograft tumor model, and cancer stem cell (CD44+ cell) analysis platform 1.High expression in pancreatic ductal adenocarcinoma (PDAC). UpregulationTherapy: PDE3A inhibitor and EGCG (via 67LR) combination therapy Kumazoe et al. 2016
2.A combined therapy utilizing the cGMP-inducing agent EGCG (via 67LR) along with PDE3A inhibition potently suppresses the CD44/FOXO3 axis, inhibits liver metastasis in vivo, and prolongs survival.  
GIST Molecular mechanism research, drug development, combined therapy research, regulation of tumor microenvironment, gene function research Gastrointestinal stromal tumor cell lines (including imatinib-sensitive and -resistant strains), patient-derived xenograft models, clinical tumor tissue samples, gene-editing cell models, mouse disease models 1. High expression in gastrointestinal stromal tumors (GISTs). Upregulation Takaki et al. 2024
2. PDE3A and SLFN12 are highly expressed in gastrointestinal stromal tumors. Molecular glues such as OPB-171775 and DNMDP induce the formation of a PDE3A-SLFN12 complex, activating SLFN12’s ribonuclease activity to degrade tRNA, inhibit protein synthesis, and trigger the GCN2 pathway-mediated cell death. Promoting proliferation and metastasis (ETV1) Nazir et al. 2017
3. PDE3A inhibitor cytotoxicity in GIST involves YAP suppression via a cAMP-independent mechanism. Coexpression of PDE3A and SLFN12 Vandenberghe et al. 2019
4. PDE3A upregulation promotes M2 macrophage polarization through ETV1 induction, contributing to GIST aggressiveness. Therapy: Molecular glues (OPB-171775 and DNMDP) Pulkka et al. 2018 Vandenberghe et al. 2017 Thys et al. 2015 Guo et al. 2022
GC Enzyme activity analysis, clinical correlation study Clinical tissue samples of human gingival cancer (patients with negative/positive lymph nodes) 1.Upregulation in metastatic oral cancers with positive lymph nodes. Upregulation Promoting proliferation and metastasis Spoto et al. 2004
2.PDE3A promotes the invasion and metastasis of gingival carcinoma cells by hydrolyzing cAMP and regulating downstream signaling pathways.  
AML Research on drug mechanisms and exploration of combined treatment strategies Acute myeloid leukemia cell line, leukemia animal model with high expression of PDE3A 1. High expression in AML cells than in normal cells. Upregulation Promoting proliferation Yang et al. 2024
2. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells. Therapy:PDE3A inhibitor anagrelide (ANA), Anan-idarubicin (IDA) combination therapy
3. The Anan-idarubicin (IDA) combination therapy triggers a caspase-3-dependent cleavage of GSDME, thereby inducing pyroptosis and exerting the most significant synergistic antileukemic effect in acute myeloid leukemia (AML) cell lines with high PDE3A expression.  
VT Research on gene functions, the study of cell cycle regulation mechanisms, gene expression analysis, in vitro functional assays, computational analysis and drug activity evaluation Mouse vascular smooth muscle cell (VSMC) culture model, gene knockout cell line, hCMEC/D3 human brain microvascular endothelial cells, bioinformatics databases and algorithms Dual regulatory mechanism: 1. PDE3A inhibits the MAPK signaling pathway by regulating the inhibitory phosphorylation of Raf-1 under the action of PKA, thereby preventing the proliferation of vascular smooth muscle cells. 2. PDE3A activates the PKA/CREB pathway, thereby promoting the expression of p21. At the same time, it, together with proteins such as p53 and MKP-1, can cause the cells to enter a stationary state in the G0/G1 phase. 3.miR-27a-3p and miR-222–3p, as potential therapeutic candidates for CSVD, enhance barrier function and cerebral blood flow by targeting endothelial PDE3A. Epigenetic modification (miR-27a-3p and miR-222–3p) Inhibition of DNA synthesis and cell proliferation (VSMCs) Begum et al. 2011 S. Yasmeen et al. 2019
HCC Drug chemical synthesis and activity screening, clinical protein expression analysis Hepatocellular carcinoma cell line (Hep-G2), clinical liver tissue samples (patients with alcoholic hepatitis and nonalcoholic fatty liver disease) 1. Upregulation in alcoholic hepatitis (AH) and downregulation in nonalcoholic steatohepatitis (NASH). Variations in PDE3A, LDLR, and FOXO1 are linked to vascular invasion in hepatocellular carcinoma (HCC). Upregulation (AH) Downregulation (NASH) Promoting proliferation and metastasis Badr et al. 2017 Lu et al. 2018
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a

BC: breast cancer; CC: cervical cancer; MLPS: myxoid liposarcoma; SCCE: esophageal small cell carcinoma; OS: osteosarcoma; OC: ovarian carcinoma; THCA: thyroid carcinoma; M: melanoma; LC: lung cancer; PDAC: pancreatic ductal adenocarcinoma; GIST: gastrointestinal stromal tumors; GC: human gingival squamous cell carcinoma; AML: acute myeloid leukemia; VT: vascular tumors; HCC: hepatocellular carcinoma.

4.4. PDE3A and Cell Proliferation

PDE3A regulates the growth of vascular smooth muscle cells (VSMCs) through two complementary pathways: PKA-catalyzed inhibitory phosphorylation of Raf-1 leads to suppression of MAPK signaling and PKA/CREB-mediated induction of p21, resulting in G0/G1 cell cycle arrest, as well as increased accumulation of p53, MKP-1, p21, and WIP1, inhibiting the progression of the cell cycle from G1 to S. These mechanisms collectively significantly reduce DNA synthesis and cell proliferation in VSMCs, providing a potential therapeutic target for preventing vascular diseases (such as atherosclerosis, vascular restenosis) and vascular tumors.

4.5. PDE3A-SLFN12 Interaction and Cell Death

4.5.1. Cytotoxic Effects and Molecular Mechanisms Mediated by the PDE3A-SLFN12 Interaction

The interaction between PDE3A and SLFN12 can specifically induce the death of cancer cells with high coexpression of both proteins. Studies have shown that SLFN12 inherently possesses RNase activity, and its binding to PDE3A remarkably enhances this nuclease activity, which serves as the core driver of the cytotoxic response in cancer cells. − Further investigations revealed that the formation of the PDE3A-SLFN12 complex triggers the dephosphorylation of SLFN12 (Ser368 and Ser573), which not only increases the protein stability of SLFN12 but also enhances its rRNA degradation activity, ultimately leading to cancer cell death by disrupting ribosomal function and protein synthesis. In addition, the elevated level of SLFN12 binds to ribosomes, thereby preventing the recruitment of signal recognition particles (SRPs) and ultimately inhibiting the protein translation process of Bcl-2 and Mcl-1, which in turn triggers cell apoptosis. The sensitivity of cytotoxic effect is strictly dependent on the coexpression levels of PDE3A and SLFN12. Among 766 cancer cell lines, the sensitivity to DNMDP was positively correlated with PDE3A expression, and SLFN12 coexpression was a necessary condition for maintaining this sensitivity. Knockdown of either gene alone resulted in the development of drug resistance in cancer cells. Furthermore, PDE3B can also interact with SLFN12 and support DNMDP sensitivity in the absence of PDE3A, suggesting a certain degree of cross-reactivity among family members in this interaction mechanism.

4.5.2. Induction Mechanism of the PDE3A-SLFN12 Interaction

The catalytic domain of PDE3A can bind to the C-terminal α-helix of SLFN12 to form a heterotetrameric complex, and small molecules such as DNMDP can act as “molecular glues” to further stabilize this interaction. Other known compounds of the “molecular glue” such as BRD9500, estradiol, anagrelide, nauclefine, and a variety of progesterone receptor agonists ,,,− (Figure ). Notably, the catalytic activity of PDE3A is not a necessary condition for complex formation; however, the complete expression of its catalytic domain is crucial for DNMDP binding and complex assembly. Mutations in the active site will lead to the loss of the compound’s binding ability, thereby blocking the occurrence of the interaction. , In addition, the cochaperone protein AIP has been confirmed to be an essential factor for the formation of the PDE3A-SLFN12 complex. CRISPR screening results showed that AIP deficiency significantly affect the DNMDP-induced PDE3A-SLFN12 interaction and subsequent cellular responses.

3.

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Cytotoxic effects and molecular mechanisms mediated by the PDE3A-SLFN12 interaction. The catalytic domain of PDE3A can bind to the C-terminal α-helix of SLFN12 to form a heterotetrameric complex, and small molecules such as DNMDP can act as “molecular glues” to further stabilize this interaction. The PDE3A-SLFN12 complex triggers the dephosphorylation of SLFN12 (Ser368 and Ser573), which not only increases the protein stability of SLFN12 but also enhances its tRNA degradation activity, ultimately leading to cancer cell death by disrupting ribosomal function and protein synthesis. Reprinted with permission from [Chen, Jie et al. Nature communications vol. 12,1 6204. Twenty-seven Oct. 2021, doi:10.1038/s41467–021–26546–8]. Copyright © 2021, Figure was published by the Springer Nature.

4.6. PDE3A and Metastasis and Invasion

PDE3A plays a crucial role in the lymph node metastasis of gingival cancer. The background of the study is based on the key role of PDE in intracellular signal transduction, which regulates the intracellular signaling process by hydrolyzing cAMP and cGMP. Therefore, the researchers analyzed the PDE and cAMP activities in lymph node-negative (N(−)) and lymph node-positive (N­(+)) patients with gingival cancer, and detected the expression level of PDE3A using immunohistochemical methods. The results showed that there were significant differences in PDE activity between the N(−) group and the N­(+) group compared to the normal control group. The PDE activity of the N­(+) group was more significantly different from that of the control group (p = 0.0156), and the difference between the N(−) group and the control group was also statistically significant (p = 0.0433). This indicated that changes in PDE activity may be related to the invasion and lymph node metastasis of gingival cancer. In addition, the immunohistochemical analysis of PDE3A also showed a significant difference between the N(−) group and the N­(+) group (p = 0.0397), which further supports the important role of PDE3A in the progression of gingival cancer.

Furthermore, PDE3A promotes the translocation of CCDC88A from the cytoplasm to the nucleus, thereby promoting the invasive metastasis cascade of breast cancer. The selective PDE3A inhibitor cilostazol significantly inhibited the growth of breast tumors and reduced lung metastasis in xenografted breast cancer models, with minimal toxicity.

Another article studied the process by which ALDOA coordinates PDE3A through the β-catenin/ID3 axis to promote cancer metastasis and M2 macrophage polarization in lung cancer with EGFR mutations. It was found that in lung cancer patients with EGFR mutations, the expression of ALDOA is abnormal, leading to dysfunction and affecting related metabolic processes. Through multiomics analysis (including transcriptomics, proteomics, and pulldown experiments), a significant correlation was found between PDE3A and ALDOA, and they affect the polarization of M2 macrophages through β-catenin and its downstream ID3. M2 macrophages are a subpopulation of cells with immunosuppressive characteristics that play an important role in the tumor microenvironment, promoting tumor progression and metastasis. Additionally, it was found that the PDE3A inhibitor trequinsin can reduce the polarization state of M2 macrophages in lung cancer cell lines with EGFR mutations and decrease cell migration, invasion, and metastasis.

It was reported that PDE3A was significantly correlated with the OS of HCC patients and association with vascular invasion. This study used targeted next-generation sequencing (tNGS) with a 603-cancer-gene panel to analyze 232 HCC and 22 intrahepatic cholangiocarcinoma patients, including 47 unresectable/metastatic HCC patients treated with anti-PD-1 plus bevacizumab. Results showed PDE3A, LDLR, and FOXO1 alterations are linked to HCC vascular invasion, and PDE3A can serve as a novel biomarker for HCC progression, recurrence, and response to immunotherapy.

From these results, it can be inferred that PDE3A may affect intracellular signaling by regulating cAMP levels, thereby influencing the growth, differentiation, and metastasis of cancer cells, especially in patients with lymph node metastasis. Therefore, PDE3A is not only a potential biomarker that can be used to assess the invasiveness and prognosis of cancer but also a potential therapeutic target.

4.7. PDE3A and Cancer Stemness

Na Hao et al. showed that PDE3A can act as a mediator of cancer stem cells­(CSCs), making breast cancer patients prone to metastasis. It was found that PDE3A inhibits the cAMP/PKA-induced inflammatory nuclear factor NF-κB signaling pathway, promoting the expression of the stem cell marker OCT4. Therefore, PDE3A is a potential therapeutic target for advanced breast cancer.

A team of researchers discovered that PDE3A is closely related to the characteristics of CSCs in pancreatic ductal adenocarcinoma (PDAC). PDE3A is overexpressed in CD44+ cells of PDAC, and CD44 is a key marker of CSCs. This indicated that PDE3A may play an important role in maintaining the characteristics of CSCs. Through immunofluorescence staining and Western blotting, the study further confirmed the positive correlation between PDE3A and CD44 expression, suggesting that the high expression of PDE3A may affect the self-renewal, proliferation, and survival characteristics of CSCs by regulating the expression of CD44 or its related signaling pathways.

Furthermore, the study also found that the inhibitor of PDE3A could significantly enhance the inhibitory effect of EGCG (epicatechin gallate) on CSCs. This combined treatment significantly weakened the characteristics of CSCs by inhibiting the FOXO3 and CD44 axis. FOXO3 is a key transcription factor closely related to the self-renewal and survival of CSCs, while CD44 is an important marker of CSCs. The combined use of PDE3A inhibitor and EGCG could significantly increase the intracellular cGMP level, thereby regulating downstream signaling pathways to inhibit the characteristics of CSCs. This combination treatment strategy provides a new idea and direction for pancreatic cancer treatment.

4.8. PDE3A and TAM Cell in Tumor Microenvironment

Except the ALDOA coordinates PDE3A through the β-catenin/ID3 axis to promote M2 macrophage polarization in lung cancer with EGFR mutations, another study reported that PDE3A plays an important regulatory role in the M2 polarization of tumor-associated macrophages (TAMs) mediated by ETV1 and the pathological progression of GIST. The results showed a positive correlation between PDE3A and ETV1 and M2 polarization. Overexpression of PDE3A can reverse the inhibitory effect of ETV1 knockdown. This indicated that regulating the expression of PDE3A can affect the function of ETV1, thereby influencing the polarization state of TAMs and the biological behavior of GIST cells. This finding suggests that inhibiting ETV1 or regulating the expression of PDE3A to intervene in TAM polarization, thereby inhibiting the malignant progression of GIST, which providing a new potential target for GIST treatment.

4.9. PDE3A and Therapeutic Resistance

As mentioned earlier, PDE3A is downregulated in cisplatin-resistant NSCLC cells, and forced expression of PDE3A can enhance the sensitivity of A549 cells to cisplatin, indicating that PDE3A may play an important role in chemotherapy resistance of lung cancer cells.

Studies confirmed a novel molecular glue OPB-171775-regulating the PDE3A-SLFN12 interaction – could effectively inhibit tumor growth in tyrosine kinase inhibitor (TKI)-resistant and other GIST subtypes. As a novel non-TKI agent, OPB-171775 represents a promising candidate for treating TKI-resistant GIST. Mechanically, OPB-171775 binds to PDE3A, inducing PDE3A-SLFN12 complex formation; this stabilizes SLFN12, preventing its proteasomal degradation and promoting intracellular accumulation. SLFN12 exerts RNase activity to target tRNA, causing tRNA dysfunction/degradation and subsequent global protein synthesis inhibition. This triggers cellular stress, activating the GCN2 signaling pathway and ultimately leading to cell cycle arrest and death. Verified in vitro, this mechanism exhibits potent antitumor effects in GIST patient-derived xenograft (PDX) modelsregardless of KIT mutation status.

Additionally, other studies have shown that PDE3A inhibitors can weaken the activity of GIST cells. Therefore, researcher continued to study that the PDE3A inhibitor cilostazol can enhance the inhibitory effect of imatinib on GIST cells, showing a synergistic effect in both imatinib-sensitive GIST882 cell lines and imatinib-resistant GIST48 cell lines. Cilostazol induces the nuclear exclusion of YAP through a cAMP-independent mechanism, thereby inactivating it. Moreover, the YAP/TEAD interaction inhibitor verteporfin can significantly reduce the survival rate of GIST882 and GIST48 cells, further emphasizing the potential application value of PDE3A or YAP-targeted drugs in combination therapy to overcome GIST resistance.

4.10. PDE3A and Tumor Metabolism

Researchers used normal human osteoblasts (NHOst) and SaOS-2 osteosarcoma cells for experiments. The cells were cultured in specific media and treated under certain conditions. The types and subtypes of PDE were then identified. It was found that PDE3A is expressed and functional in NHOst cells, regulating cAMP levels through hydrolysis and significantly affecting cAMP accumulation stimulated by PGE2. In SaOS-2 cells, although PDE3A mRNA was detected, its activity was not, indicating that PDE3A may not be functional in these cells. The difference in PDE3A activity may be related to bone metabolism and the biological characteristics of bone tumors, providing important clues for understanding the role of phosphodiesterase inhibitors in bone metabolism.

4.11. PDE3A and Tumor Immunology

As mentioned earlier, PDE3A was a novel genetic alterations in liver cancer distinguish distinct clinical outcomes and combination immunotherapy responses. The study performed comprehensive genomic profiling of 232 HCC and 22 intrahepatic cholangiocarcinoma patients using targeted next-generation sequencing (tNGS) with a 603-cancer-gene panel, focusing on 47 unresectable/metastatic HCC patients treated with anti-PD-1 plus bevacizumab. In immunotherapy response, high tumor mutational burden (TMB), PTPRZ1 alterations, and cell cycle-related alterations are associated with higher objective response rates (ORR) and better PFS, whereas KMT2D alterations are correlated with inferior PFS. This study uncovers subtype-specific genomic drivers, identifies novel prognostic biomarkers for liver cancer progression and recurrence, and provides predictive genetic markers for anti-PD-1 plus bevacizumab response, laying the groundwork for personalized clinical management.

4.12. PDE3A Inhibition and as Cancer Target

The distinctive expression pattern and functional roles of PDE3A make it an attractive therapeutic target. Several strategies have been explored, including direct inhibition of PDE3A catalytic activity, disruption of PDE3A-SLFN12 interaction, and combination therapy with existing anticancer agents.

Cilostazol, a clinically approved PDE3 inhibitor, has shown promising preclinical efficacy in GIST, reducing cell viability and synergizing with imatinib (combination index CI50 = 0.15). This synergism allows for dose reduction of both drugs, potentially minimizing adverse effects associated with high-dose imatinib. In GIST xenograft models, cilostazol monotherapy inhibits tumor growth, and its combination with imatinib results in enhanced antitumor activity.

In squamous cell carcinoma, PDE3A is overexpressed alongside PDE2A, and PDE3A inhibition disrupts the cAMP-PKA signaling pathway linked to ERK and AKT, triggering apoptotic cell death. PDE3A also contributes to imatinib resistance in GIST by modulating the YAP pathway; its inhibition induces YAP nuclear exclusion, overcoming treatment resistance. Additionally, novel pyridine derivatives demonstrate that PDE3A inhibition correlates directly with cytotoxicity in MCF-7 and HeLa cells, validating its role as a driver of tumor growth.

Its noncatalytic functionforming a cytotoxic PDE3A-SLFN12 complexinduces apoptosis, and noncatalytic targeting of PDE3A-SLFN12 through molecular glue compounds represents a novel therapeutic approach. To date, various PDE3A modulators have been confirmed to exert anticancer activity by promoting the PDE3A-SLFN12 interaction. ,,,− OPB-171775, a small molecule that induces PDE3A-SLFN12 complex formation, exhibits potent efficacy against GIST patient-derived xenografts (PDX) regardless of KIT mutation status, including imatinib-resistant models. This agent acts by stabilizing SLFN12, leading to ribosomal stress, GCN2 pathway activation, and ultimately cell death. In vivo studies demonstrate that OPB-171775 induces tumor regression in GIST PDX models and achieves complete tumor eradication when combined with imatinib. Similarly, DNMDP selectively kills PDE3A/SLFN12-coexpressing cancer cells, with an IC50 of 27 nM in GIST882 cells, validating the therapeutic potential of this interaction.

4.13. Application Prospects in Tumor Therapy

The interaction between PDE3A and SLFN12 provides a novel target and strategy for precision tumor therapy. Clinical sample analysis revealed that both PDE3A and SLFN12 are highly expressed in MLPS, particularly in high-grade tumors. MLPS cell lines with coexpression of these two genes exhibit high sensitivity to PDE3A modulators. This finding indicates that the coexpression of PDE3A and SLFN12 can serve as a biomarker for screening cancer patients sensitive to PDE3A modulators, offering a new therapeutic direction for MLPS and other tumor subtypes lacking effective precision treatment options. Such compounds hold great potential for development as novel targeted anticancer drugs, especially for tumor subtypes with high PDE3A and SLFN12 coexpression.

Anagrelide, another PDE3 inhibitor approved for thrombocythemia, has shown efficacy in GIST xenograft models, including those harboring KIT exon 9 mutations that require high-dose imatinib. In preclinical studies, anagrelide reduced tumor volume by 68% in KIT exon 9 mutant GIST models, outperforming imatinib at standard doses. This suggests that PDE3A inhibitors may provide an alternative treatment option for patients with imatinib-intolerant or resistant disease.

Despite these promising findings, several challenges remain in translating PDE3A-targeted therapy to clinical practice. First, the tissue-specific expression of PDE3A requires robust biomarkers to identify patients most likely to benefit from treatment. Coexpression of PDE3A and SLFN12 has emerged as a predictive biomarker for response to molecular glue compounds, as demonstrated by the fact that only double-positive cancer cells are sensitive to OPB-171775 and DNMDP. Second, potential off-target effects of PDE3 inhibitors, particularly on cardiovascular function, require careful monitoring in clinical trials. However, the dose reduction enabled by combination therapy may mitigate these risks.

Future research directions should focus on expanding the understanding of PDE3A’s role in additional cancer types, elucidating the molecular mechanisms underlying its oncogenic functions, especially functions other than hydrolysis and optimizing therapeutic strategies. For instance, the role of PDE3A in succinate dehydrogenase (SDH)-deficient GIST, a subtype with no effective targeted therapies, warrants investigation given the coexpression of PDE3A and SLFN12 in diverse GIST histologies. Additionally, further characterization of PDE3A isoforms and their interactions with other signaling molecules may reveal novel therapeutic vulnerabilities.

In conclusion, PDE3A has emerged as a key mediator of cancer development, with dysregulated expression and function observed in multiple cancer types. Its dual role as a cyclic nucleotide regulator and a molecular scaffold for oncogenic protein interactions provides unique opportunities for targeted therapy. Preclinical studies demonstrate the efficacy of PDE3A inhibitors and molecular glue compounds, either alone or in combination with existing agents, highlighting their potential to address unmet clinical needs in cancer treatment. With continued translational research, PDE3A-targeted therapies may soon become a valuable addition to the oncology armamentarium.

Acknowledgments

We thank Dr. N. Hao, Department of breast surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, provide research ideas. We thank the financial support from The National Natural Science Foundation of China. We acknowledge the assistance of Figdraw (www.figdraw.com) in scientific illustration drawing.

All the studies mentioning PDE3A and its association with cancer were retrieved from PubMed.

#.

S.P. and Q.Z. contributed equally to this manuscript. S.P. and Q.Z. contributed equally to this work and conceived the review, performed the literature search and screening, designed the structure, and wrote and revised the manuscript. N.H., as the corresponding author, oversaw data quality control, provided statistical guidance, verified the results, and critically reviewed the final manuscript. B.C. conducted quality assessment and data extraction. M.M. created the figures, performed auxiliary statistical analyses. J.X. translated and polished the English abstract and standardized the reference formatting. J.L. collected additional literature, prepared the appendix, and assisted with formatting and submission. X.T., interpreted the key findings, and critically reviewed the final manuscript. All authors have read and approved the final manuscript.

This work was supported by grants from National Nature Science Foundation of China (NSFC) (82003183, to Na. Hao).

The current research was ratified by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University.

The authors declare no competing financial interest.

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Associated Data

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Data Availability Statement

All the studies mentioning PDE3A and its association with cancer were retrieved from PubMed.

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