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. Author manuscript; available in PMC: 2025 May 31.
Published in final edited form as: Adv Cancer Res. 2023 Mar 30;160:1–15. doi: 10.1016/bs.acr.2023.03.001

PFKP: More than phosphofructokinase

Haizhen Wang a,b,*, Tiffany Penaloza a,1, Amanda J Manea a,1, Xueliang Gao a,b,*
PMCID: PMC12125951  NIHMSID: NIHMS2082436  PMID: 37704285

Abstract

Phosphofructokinase (PFK) is one of the key enzymes that functions in glycolysis. Studies show that PFKP regulates cell proliferation, apoptosis, autophagy, cell migration/metastasis, and stemness through glycolysis and glycolysis-independent functions. PFKP performs its function not only in the cytoplasm, but also at the cell membrane, on the mitochondria, at the lysosomal membrane, and in the nucleus. The functions of PFKP are extensively studied in cancer cells. PFKP is also highly expressed in certain immune cells; nevertheless, the study of the PFKP’s role in immune cells is limited. In this review, we summarize how the expression and activity of PFKP are regulated in cancer cells. PFKP may be applied as a prognostic marker due to its overexpression and significant functions in cancer cells. As such, specifically targeting/inhibiting PFKP may be a critical and promising strategy for cancer therapy.

1. Introduction

PFK-1 is one of the rate-limiting enzymes of glycolysis, and it catalyzes the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphophate. PFK-1 consists of three isoforms: PFKM (muscle type), PFKL (liver type), and PFKP (platelet type). The three isoforms of PFK-1 have a high similarity of the amino acid sequences at the N- and C- terminal domains (Vora, Halper, & Knowles, 1985). PFKP is highly expressed in certain types of cancers, such as lung cancer (Shen et al., 2020), breast cancer (Wang et al., 2013), T- and B- cell leukemia (Wang et al., 2017), and ascites tumor (Sanchez-Martinez & Aragon, 1997). Importantly, data analysis from the Human Protein Atlas shows that PFKP expression is negatively associated with overall survival in cervical cancer, head and neck cancer, liver cancer, lung cancer, pancreatic cancer, renal cancer, and urothelial cancer (https://www.proteinatlas.org/ENSG00000067057-PFKP/pathology) (Table 1), suggesting that PFKP may be used as a prognostic marker for these cancers. Understanding the cellular functions of PFKP will help to develop novel and efficient strategies to target PFKP for cancer therapy.

Table 1.

PFKP expression (RNA) associated with the overall survival of cancer patients.

PFKP expression vs Overall survival Tumor type P value
Positively correlated Stomach cancer 0.026
Not correlated Breast cancer, Colorectal cancer, Endometrial cancer, Glioma, Melanoma, Ovarian cancer, Prostate cancer, Testis cancer, Thyroid cancer 0.12, 0.058, 0.17, 0.13, 0.24, 0.085, 0.088, 0.097, 0.21
Negatively correlated Cervical cancer, Head and neck cancer, Liver cancer, Lung cancer, Pancreatic cancer, Renal cancer, and Urothelial cancer. 0.0024, 0.00015, 0.0000087, 0.0014, 0.024, 0.006 0.0045
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Note: Data were collected by 2/28/2023.

2. Biological functions of PFKP

PFKP promotes cancer progression by regulating cell proliferation, apoptosis, autophagy, cell migration/metastasis, stemness, and reshaping the tumor microenvironment.

2.1. PFKP in cell growth and proliferation

Cancers rely on the glycolysis metabolic pathway to generate ATP and other metabolites. The generated energy and metabolites are critical for cancer cell growth. As the key enzyme in glycolysis, the expression of PFK-1 affects cell growth and cell proliferation. PFKP, one of the isoforms of PFK-1, is often overexpressed in cancer cells. The following studies show that PFKP regulates cell proliferation. Tat activating regulatory DNA-binding protein (TARDBP) inhibits PFKP expression through mir-520 to downregulate glycolysis, which leads to the growth inhibition of hepatocellular carcinoma cells (HCC) (Park et al., 2013). PFKP expression is upregulated in hepatocellular carcinoma, contributing to HCC proliferation and stemness maintenance (Sha et al., 2021). In brain tumors, PFKP is phosphorylated at Y64 by activated EGFR. The interaction of phosphorylated PFKP with p85a leads to PI3K activation and tumor cell proliferation (Lee et al., 2018). PFKP is the predominant isoform of PFK-1 in clear cell renal cell carcinoma (ccRCC), and is upregulated to promote ccRCC proliferation through increasing glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle (Wang et al., 2016).

2.2. PFKP in cell apoptosis/survival

Studies show that PFKP downregulation/inhibition stimulates the pentose phosphate pathway (PPP) to protect cells from apoptosis. Our study shows that cyclin D3/CDK6 phosphorylates and inhibits PFKP and PKM2 to re-direct the glycolytic intermediates into the pentose phosphate pathway and serine synthesis pathway, generating antioxidants NADPH and glutathione to decrease intracellular ROS levels and prevent apoptosis in cancer cells (Wang et al., 2017). A recent study shows that F-box protein only 7 (Fbxo7) inhibits PFKP and glycolysis to increase T-cell viability and activation, which is mediated through CDK6 activation (Harris et al., 2022). Snail, a key repressor of epithelial-mesenchymal transition, downregulates PFKP expression at the transcriptional level. This regulation leads to the switch of the glucose flux to PPP and protects cancer cells from apoptosis (Kim et al., 2017). Interestingly, PFKP regulates non-small cell lung cancer (NSCLC) cell survival in alternative ways. PFKP is upregulated in NSCLC, and its expression is associated with lymph node metastasis. PFKP overexpression blocks programmed cell death of NSCLC. This suggests that PFKP may play a distinct role in NSCLC to regulate cancer cell survival, which differs from other cancer cells (Wang, Li, & Zhang, 2021). Indeed, in NSCLC, the interaction between PFKP and AMPK stimulates the recruitment of AMPK to mitochondria to phosphorylate acetyl-CoA carboxylase 2 and increase the oxidation of long-chain fatty acid. This glycolysis-independent function of PFKP maintains the energy and redox homeostasis to promote NSCLC cell survival (Chen et al., 2022).

2.3. PFKP in autophagy

Autophagy is a conserved process that removes aggregated or misfolded proteins, clears damaged organelles, and eliminates intracellular pathogens. Autophagy also functions in cellular senescence, genome stability, antigen presentation, and necrosis. Autophagy plays significant roles in multiple diseases such as cancer, autoimmune disease, and neurodegeneration (Yu, Chen, & Tooze, 2018). Studies showed that PFKP carries out significant functions in autophagy. The degradation of PFKP induced by Salvia miltiorrhiza-derived Sal-miR-58 leads to the inactivation of Akt/mTOR signaling, which facilitates autophagy in vascular smooth muscle cells (Qin et al., 2020). However, the role of PFKP in autophagy seems different in other cell types. PFKP is upregulated in autophagy induced by starvation, and depletion of PFKP inhibits autophagy in oral squamous cell carcinoma (Chen et al., 2018). Cysteine protease ATG4B stimulates autophagosome maturation to facilitate autophagy. Amino acid deprivation leads to the enhanced interaction between PFKP and ATG4B, and PFKP functions as a protein kinase to phosphorylate ATG4B to increase its activity. The phosphorylation of PFKP at S386 plays a critical role in regulating ATG4B phosphorylation. Of note, PFKP loss partially inhibits the autophagic flux in HEK293T cells following amino acid deprivation (Li, Sun, Yan, & Yan, 2021).

2.4. PFKP in cell migration and metastasis

PFKP has been shown to regulate cancer cell migration and metastasis. The expression of PFKP, but not PFKL or PFKM, is associated with the overall survival of breast cancer patients. PFKP regulates breast cancer cell migration/metastasis through multiple mechanisms. PFKP is positively regulated by β-catenin to control lactate production in breast cancer cells, and the blocking of β-catenin decreases PFKP expression and lactate production to impair cell migration (Prasad, Sodergren, & Andersson, 2017). PFKP regulates intracellular citrate accumulation in conjunction with citrate synthase to enhance triple-negative breast cancer cell invasion and metastasis (Peng et al., 2019). HMG-CoA reductase degradation1 (HRD1) targets PFKP for ubiquitination and degradation to decrease aerobic glycolysis and cancer cell invasion/metastasis, suggesting that PFKP plays a significant role in breast cancer progression through the regulation of glycolysis (Fan et al., 2021). Snail represses PFKP at the transcriptional level, and Snail depletion leads to the upregulation of transcription, protein expression, and kinase activity of PFKP in breast cancer cells. Therefore, upregulation of Snail decreases PFKP expression, shunting glycolysis to the pentose phosphate pathway, and resulting in the generation of biosynthetic materials such as NADPH and ribose-5-phosphate to stimulate cancer cell survival and promote cancer metastasis (Kim et al., 2017). Our study shows that PFKP is translocated into the nucleus in T-cell lymphoblastic leukemia (T-ALL) to stimulate CXCR4 expression by interacting with c-myc. The upregulation of CXCR4 by nuclear PFKP facilitates T-ALL migration/infiltration into different organs. Importantly, nuclear PFKP is found in invasive T cell malignancy, but not in nonmalignant T lymph nodes or reactive hyperplasia (Gao et al., 2021). This suggests that nuclear PFKP may be applied as a prognostic marker for T-cell malignancy.

2.5. PFKP in stemness and tumor immune microenvironment

PFKP also contributes to the maintenance of stemness. Voltage-dependent anion channel 2 (VDAC2) is a mitochondrial membrane protein that regulates cell metabolism, apoptosis, and immune response et al. VDAC2 interacts with PFKP on mitochondrion to inhibit glycolysis for glioma stem cell maintenance (Zhou et al., 2018). Moreover, PFKP regulates stemness in hepatocellular carcinoma cells, contributing to HCC progression (Sha et al., 2021).

In addition, a recent study shows that PFKP expression is associated with immune cell infiltration. PFKP is highly expressed in ccRCC, which is related to the infiltration of multiple immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (DCs). This suggests that PFKP expression in cancer cells may facilitate immune therapy response in ccRCC, leading to an increased survival rate of patients (Liu et al., 2021).

3. PFKP functions at various cellular locations

As glycolysis occurs in the cytoplasm, it naturally follows that PFKP functions in the cytoplasm; however, PFKP localizes in multiple additional subcellular locations. Here, we summarize the functions of PFKP at the cell membrane, mitochondria, lysosome membrane, and nucleus.

3.1. Cell membrane

A study shows that PFKP is present in the membrane of cancer cells (Lee et al., 2018). PFKP is acetylated at K395 via lysine acetyltransferase 5. The acetylated PFKP is then translocated to the plasma membrane and phosphorylated at Y64 by activated EGFR. Phosphorylated PFKP interacts with p85a at SH2 domain and recruits p85a to the plasma membrane, activating PI3K pathway to increase tumor cell proliferation and brain tumorigenesis.

3.2. Mitochondrion

PFKP is found on the mitochondria as well. In non-stem glioblastoma cells, PFKP is recruited to mitochondria via interacting with a mitochondrial membrane protein, VDAC2. This regulation limits the amount of cytoplasmic PFKP, decreasing glycolytic activity. VDAC2 disruption releases PFKP back to the cytoplasm and reprograms glucose metabolism to induce the transition of non-stem tumor cells to glioma stem cells. This glycolytic reprogramming is prevented by a PFK-1 inhibitor, compromising the effect of VDAC2 disruption (Zhou et al., 2018).

3.3. Lysosomal membrane

One study shows that PFK-1, including PFKP, localizes at the lysosomal surface. The transient interaction between PFK-1 and the lysosome may switch glucose catabolism to mTORC1 activity. This study suggests that the PFK-1 containing glycolytic metabolon may function as a sensor to switch glucose catabolism towards mTORC1 activity through its transient interaction with the lysosome (Almacellas et al., 2019).

3.4. Nucleus

PFKP also localizes in the nucleus. Studies show that PFKP interacts with YAP/TAZ transcription cofactors TEADs to stimulate cooperation with YAP/TAZ in the nucleus to regulate their transcriptional activity (Enzo et al., 2015). Our study shows that high amounts of PFKP exist in nuclei of diverse cancer cells, including T-cell malignancy. PFKP interacts with multiple proteins functioning in the nucleus. We also found that PFKP is a nucleocytoplasmic shuttling protein with its nuclear export sequence (NES) and nuclear localization sequence (NLS). Cyclin D3/CDK6 phosphorylates PFKP and facilitates PFKP nuclear translocation by dimerization of PFKP and exposing its NLS to induce the interaction between PFKP and importin. After PFKP translocates into the nucleus, it interacts with c-Myc to stimulate the expression of C-X-C chemokine receptor type 4 to promote T-ALL cell invasion (Broxmeyer, 2021; Gao et al., 2021).

4. PFKP in immune cells

PFKP is also expressed in non-cancer cells, such as immune cells. The following is a brief summary of the studies of PFKP in immune cells.

4.1. PFKP in T cells and dendritic cells

One study shows that Fbxo7 inhibits PFKP and glycolysis to increase T-cell viability and activation. This mechanism is mediated through CDK6 activation (Harris et al., 2022). Upon the stimulation of anti-CD3 and anti-CD28 antibodies, CD4+ and CD8+ T cells increase the expression of PFKP and GAPDH to increase glycolytic flux. This suggests that PFKP expression may play a role in T-cell activation (Jones et al., 2017). Another study suggests that a high-fat diet shifts intracellular metabolism in Toll-like receptor (TLR)-activated DCs and exacerbates skin inflammation via the regulation of IL23 expression. Though lactate secretion is decreased when both PFKL and PFKP are inactivated, this inactivation does not affect IL23 expression in DCs. Upper glycolysis inhibition, such as hexokinase (HK) inhibition, stimulates IL23 expression. This result suggests that lower glycolysis is not essential in regulating IL23 expression and exacerbating skin inflammation (Mogilenko et al., 2019).

4.2. PFKP expressed in multiple immune cells

Data derived from the Human Protein Atlas show that PFKP is highly expressed in several types of immune cells (https://www.proteinatlas.org/ENSG00000067057-PFKP/immune+cell). PFKP and PFKL are highly expressed in immune cells, such as T cells, B cells, NK cells, and DCs, suggesting that they may play critical roles in those immune cells. PFKP and PFKL are upregulated in memory CD4+ and CD8+ T cells compared to corresponding naïve T cells, suggesting PFKP and PFKL may regulate T-cell memory formation. The glycolysis pathway has three rate-limiting enzymes: hexokinase (HK), PFKP, and pyruvate kinases type M (PKM). Interestingly, the expressions of HK and PKM are not upregulated in memory T cells (Fig. 1). Future studies may focus on exploring the role of PFKP in memory T cells and the regulatory function of PFKP in memory T-cell differentiation.

Fig. 1.

Fig. 1

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PFK-1 (PFKP, PFKL, PFKM) expression in different types of immune cells.

5. The regulation of PFKP expression

The expression of PFKP can be regulated at the transcriptional, translational, and post-translational levels. PFKP expression is regulated at the transcriptional level by multiple transcription factors. The transcription factor Krüppel-like factor 4 (KLF4) binds to the PFKP promoter region to activate PFKP expression to upregulate glycolytic metabolism, and this regulation is specific to PFKP, but not PFKL or PFKM (Moon et al., 2011). TARDBP, a transcriptional repressor, is also an RNA-binding protein functioning in RNA processing and metabolism. In hepatocellular carcinoma, TARDBP suppresses mir-520 expression to inhibit PFKP expression and downregulate glycolysis (Park et al., 2013). Snail, a transcriptional repressor, represses PFKP transcription, and as mentioned earlier, upregulation of Snail drives cancer metastasis (Kim et al., 2017). Moreover, Zinc Finger and BTB domain-containing protein 7A (ZBTB7A) binds to the promoter region of PFKP to repress its transcription to decrease glycolysis in cancer cells (Liu et al., 2014). Methylation in CpG islands also affects gene expression. In HER2-positive breast cancer cells, a hypomethylation of CpGs in the gene bodies of PFKP was found, indicating that methylation in CpGs may regulate PFKP expression (Lindqvist, Wingren, Motlagh, & Nilsson, 2014). In breast cancer, PFKP expression is also repressed by BRCA1/ZBRK1 at the transcriptional level (Yeerken et al., 2020).

The expression of PFKP can be regulated at the translational level. For example, PFKP expression is regulated by HIF-1α to reprogram metabolism in TNBC breast cancer (Peng et al., 2019). HIF-1α also modulates PFKP expression in mature brown adipocytes, as knockdown HIF-1α reduces PFKP expression (Basse et al., 2017).

Post-translational modifications also affect PFKP expression. In human glioblastoma, activated AKT phosphorylates PFKP at S386 to inhibit the interaction between TRIM21 E3 ligase and PFKP. PFKP protein stability increases as TRIM21-dependent polyubiquitination at K10 decreases, which increases the PFKP protein amount, promoting aerobic glycolysis and brain tumor growth (Lee et al., 2017). In addition, HRD1 facilitates PFKP ubiquitination at K10 and promotes PFKP degradation, suggesting that HRD1 decreases aerobic glycolysis in breast cancer cells to inhibit breast cancer progression (Fan et al., 2021).

6. The regulation of PFKP activity

Post-translational modifications, such as phosphorylation, acetylation, and glycosylation, can regulate PFKP activity. For example, PFKP acetylation at K395 by lysine acetyltransferase 5 (KAT5) leads to PFKP translocation to the plasma membrane. EGFR then phosphorylates the membrane-translocated PFKP at Y64 to enhance PFKP activity to promote the brain tumorigenesis (Lee et al., 2018). In addition, PFKP phosphorylation at Y64 has an important role in AKT activation, β-catenin phosphorylation, and transactivation to promote brain tumor growth (Lee et al., 2020). Moreover, PFKP can function as a protein kinase to phosphorylate ATG4B at S34 to enhance ATG4B activity and p62 degradation. As noted previously, in HEK293T cells, phosphorylation of PFKP at S386 is critical for autophagy via ATG4B phosphorylation (Li et al., 2021). PFKP phosphorylation by cyclin D3/CDK6 at Ser 679 promotes PFKP dimerization to decrease its activity and increase cancer cell survival through reducing the production of NADPH and GSH (Wang et al., 2017). In addition, the dimerization of PFKP stimulates its nuclear translocation to regulate CXCR4 expression at the transcription level (Gao et al., 2021). Other examples of post-translational modifications include PFKP phosphorylation at S12 by cyclic AMP-dependent protein kinase. Though this phosphorylation does not produce significant changes in kinetic regulatory properties, it may have a role during the evolution of the enzymes (Valaitis, Foe, Kwiatkowska, Latshaw, & Kemp, 1989). Several post-translational modifications on PFKP, such as phosphorylation, acetylation, methylation, ubiquitination, and sulfoxidation of methionyl residues, have been disclosed (https://metosite.uma.es/scan/Q01813). In contrast, the biological functions of those modifications are not well studied. Future work may focus on exploring the unknown functions of those modifications on PFKP.

7. Prognostic value of PFKP and strategies to target PFKP for cancer therapy

PFKP plays a significant role in cancer progression. Here, we summarize the potential of PFKP as a prognostic marker for cancer. We also provide a rationale to develop new strategies to specifically target/inhibit PFKP for cancer therapy.

7.1. Prognostic value of PFKP

PFKP expression is negatively associated with the 5-year survival of patients with cervical, head and neck, liver, lung, pancreatic, renal, and urothelial cancer (the Human Protein Atlas). Moreover, high PFKP expression is associated with a poor prognosis in patients with lung cancer/renal cancer (Liu et al., 2021; Shen et al., 2020). Conversely, PFKP expression is positively associated with the 5-year survival of stomach cancer patients. The correlations between PFKP expression and 5-year survival in patients with other cancer types are insignificant. This suggests that PFKP expression may be a prognostic marker for certain cancers but not all.

Certain factors need to be considered to determine the prognostic value of PFKP. For example, though the Human Protein Atlas shows the correlation between PFKP expression and overall survival is not significant in breast cancer, several studies showed that PFKP might be used as a prognostic marker for subsets of breast cancer (Inaishi et al., 2022; Yeerken et al., 2020). Breast cancer is a highly heterogeneous disease, which can be divided into four major groups: luminal A, luminal B, basal-like, and HER2-enriched. These studies suggest that the subtypes of breast cancer may need to be considered separately when the prognostic value of PFKP is evaluated. Other factors, such as the age and race of the patients, should also be included. On another note, nuclear PFKP in the specimens correlated with poor survival in patients with T-cell malignancy (Gao et al., 2021), suggesting that there is a potential utility of nuclear PFKP as a diagnostic marker for T-cell malignancy. This finding also indicates that the subcellular locations of PFKP need to be considered to use PFKP as a prognostic marker in addition to cancer subtypes.

Single nucleotide polymorphisms (SNPs), PFKP rs1132173C > T, are associated with survival outcomes in non-small cell lung cancer (NSCLC) after surgical resection. This suggests SNPs (PFKP rs1132173C > T) may predict the survival of NSCLC patients after surgical resection (Lee et al., 2016). There are 44 somatic mutations of PFKP reported. Among them, R48C, N426S, and D564N are well-studied somatic mutations. The R48C mutant of PFKP decreases citrate inhibition, the N426S mutant moderately alleviates ATP inhibition, and the D564N mutant reduces its affinity for substrate (F6P). Accordingly, PFKP mutation at R48, N426, or D564 may predict the prognosis of cancer (Webb et al., 2015).

7.2. Strategies to target PFKP for cancer therapy

PFK-1 can be inhibited by several types of inhibitors. (1) Inhibitors, such as acetylsalicylic acid (ASA, aspirin), directly inhibit the activity of PFK-1 (Spitz, Furtado, Sola-Penna, & Zancan, 2009). (2) Inhibitors, such as Paclitaxel and clotrimazole, detach PFK-1 from cytoskeleton to inactivate PFK-1. These compounds indirectly inhibit PFK-1 activity (Glass-Marmor & Beitner, 1999; Zancan, Rosas, Marcondes, Marinho-Carvalho, & Sola-Penna, 2007). (3) Inhibitors that suppress Fructose-2,6-bisphosphate (F2,6BP) activity indirectly inactivate PFK-1. All these inhibitors are not selective for PFKP; as such, applying these inhibitors to target PFKP for cancer therapy may cause side effects for cancer patients. Developing compound(s) to specifically degrade PFKP may be promising for cancer therapy. Since post-translational modification and subcellular location affect the functions of PFKP, targeting the specific modification and/or subcellular localization of PFKP might also be a promising strategy for cancer therapy.

8. Conclusion and future directions

As one of the rate-limiting enzymes that function in glycolysis, PFKP regulates cell proliferation, apoptosis, autophagy, cell migration/metastasis, and stemness. PFKP can influence functions at multiple subcellular locations, including the cytoplasm, cell membrane, mitochondria, lysosomal membrane, and nucleus. Evidence shows that PFKP is not only overexpressed in cancer cells, but also expressed in immune cells. The functions of PFKP in immune cells are not well understood; however, it is clear that PFKP is upregulated in certain populations of immune cells, such as memory T cells. Exploring the functions of PFKP in immune cells may help us develop efficient therapeutic strategies for cancer patients. Moreover, PFKP expression can be regulated at the transcriptional, translational, and post-translational levels. It is important to explore the unknown but critical mechanism(s) in regulating PFKP expression in order to develop an efficient way to target/inhibit PFKP. Post-translational modifications also affect PFKP activity; however, the consequences of these modifications are still not well-studied. Future investigations may explore how these modifications influence PFKP activity to provide potential targets for therapeutic development. In addition, PFKP expression level is associated with the survival and malignancy status of patients with certain types of cancer, suggesting that PFKP is a promising prognostic marker for patients with those types of cancer. Although current compounds that inhibit the activity of PFK-1 are not selective for PFKP, developing novel PFKP-specific inhibitors may advance cancer therapy and help patients improve their health outlook.

Acknowledgments

This work was supported by the National Institutes of Health (R37CA251165) and the Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award (821901) to H.W.; the American Cancer Society Institutional Research Grant (IRG-19-137-20), the SC COBRE in Oxidants, Redox Balance and Stress Signaling Pilot Projects Program (1P30CM140964) to X. G.

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