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Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux

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Abstract

Reprogrammed metabolism and high energy demand are well-established properties of cancer cells that enable tumor growth. Glycolysis is a primary metabolic pathway that supplies this increased energy demand, leading to a high rate of glycolytic flux and a greater dependence on glucose in tumor cells. Finding safe and effective means to control glycolytic flux and curb cancer cell proliferation has gained increasing interest in recent years. A critical step in glycolysis is controlled by the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which converts fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). F2,6BP allosterically activates the rate-limiting step of glycolysis catalyzed by PFK1 enzyme. PFKFB3 is often overexpressed in many human cancers including pancreatic, colon, prostate, and breast cancer. Hence, PFKFB3 has gained increased interest as a compelling therapeutic target. In this review, we summarize and discuss the current knowledge of PFKFB3 functions, its role in cellular pathways and cancer development, its transcriptional and post-translational activity regulation, and the multiple pharmacologic inhibitors that have been used to block PFKFB3 activity in cancer cells. While much remains to be learned, PFKFB3 continues to hold great promise as an important therapeutic target either as a single agent or in combination with current interventions for breast and other cancers.

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References

  1. Warburg, O., Wind, F., & Negelein, E. (1927). The metabolism of tumors in the body. Journal of General Physiology, 8(6), 519–530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314.

    Article  CAS  PubMed  Google Scholar 

  3. Warburg, O. (1956). On respiratory impairment in cancer cells. Science, 124(3215), 269–270.

    Article  CAS  PubMed  Google Scholar 

  4. DeBerardinis, R. J., & Chandel, N. S. (2016). Fundamentals of cancer metabolism. Science Advances, 2(5), e1600200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Tanner, L. B., et al. (2018). Four key steps control glycolytic flux in mammalian cells. Cell System, 7(1), 49-62 e8.

    Article  CAS  Google Scholar 

  6. Al Hasawi, N., Alkandari, M. F., & Luqmani, Y. A. (2014). Phosphofructokinase: A mediator of glycolytic flux in cancer progression. Critical Reviews in Oncology/Hematology, 92(3), 312–21.

    Article  PubMed  Google Scholar 

  7. Van Schaftingen, E., Hue, L., & Hers, H. G. (1980). Fructose 2,6-bisphosphate, the probably structure of the glucose- and glucagon-sensitive stimulator of phosphofructokinase. The Biochemical Journal, 192(3), 897–901.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Van Schaftingen, E., Hue, L., & Hers, H. G. (1980). Control of the fructose-6-phosphate/fructose 1,6-bisphosphate cycle in isolated hepatocytes by glucose and glucagon. Role of a low-molecular-weight stimulator of phosphofructokinase. Biochemical Journal, 192(3), 887–95.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Uyeda, K., et al. (1982). Fructose-2,6–P2, chemistry and biological function. Molecular and Cellular Biochemistry, 48(2), 97–120.

    Article  CAS  PubMed  Google Scholar 

  10. El-Maghrabi, M. R., et al. (2001). 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: Suiting structure to need, in a family of tissue-specific enzymes. Current Opinion in Clinical Nutrition and Metabolic Care, 4(5), 411–418.

    Article  CAS  PubMed  Google Scholar 

  11. Crepin, K. M., et al. (1989). Cloning and expression in Escherichia coli of a rat hepatoma cell cDNA coding for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. The Biochemical Journal, 264(1), 151–160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Darville, M. I., et al. (1987). Complete nucleotide sequence coding for rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase derived from a cDNA clone. FEBS Letters, 224(2), 317–321.

    Article  CAS  PubMed  Google Scholar 

  13. Lively, M. O., et al. (1988). Complete amino acid sequence of rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Journal of Biological Chemistry, 263(2), 839–849.

    Article  CAS  PubMed  Google Scholar 

  14. Sakata, J., Abe, Y., & Uyeda, K. (1991). Molecular cloning of the DNA and expression and characterization of rat testes fructose-6-phosphate,2-kinase:Fructose-2,6-bisphosphatase. Journal of Biological Chemistry, 266(24), 15764–15770.

    Article  CAS  PubMed  Google Scholar 

  15. Sakata, J., & Uyeda, K. (1990). Bovine heart fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase: Complete amino acid sequence and localization of phosphorylation sites. Proc Natl Acad Sci USA, 87(13), 4951–4955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Manzano, A., et al. (1999). Cloning, expression and chromosomal localization of a human testis 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene. Gene, 229(1–2), 83–89.

    Article  CAS  PubMed  Google Scholar 

  17. Manzano, A., et al. (1998). Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase gene (PFKFB3). Cytogenetics and Cell Genetics, 83(3–4), 214–217.

    Article  CAS  PubMed  Google Scholar 

  18. Okar, D. A., et al. (2001). PFK-2/FBPase-2: Maker and breaker of the essential biofactor fructose-2,6-bisphosphate. Trends in Biochemical Sciences, 26(1), 30–35.

    Article  CAS  PubMed  Google Scholar 

  19. Rider, M. H., et al. (2004). 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: Head-to-head with a bifunctional enzyme that controls glycolysis. The Biochemical Journal, 381(Pt 3), 561–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chesney, J., et al. (2014). Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth. Oncotarget, 5(16), 6670–6686.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dasgupta, S., et al. (2018). Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature, 556(7700), 249–254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Goidts, V., et al. (2012). RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene, 31(27), 3235–3243.

    Article  CAS  PubMed  Google Scholar 

  23. Taylor, C., et al. (2017). Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells. Oncotarget, 8(11), 17960–17980.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ventura, F., et al. (1995). Cloning and expression of a catalytic core bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Biochemical and Biophysical Research Communications, 209(3), 1140–1148.

    Article  CAS  PubMed  Google Scholar 

  25. Sakai, A., et al. (1996). Cloning of cDNA encoding for a novel isozyme of fructose 6-phosphate, 2-kinase/fructose 2,6-bisphosphatase from human placenta. Journal of Biochemistry, 119(3), 506–511.

    Article  CAS  PubMed  Google Scholar 

  26. Sakakibara, R., et al. (1997). Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase. Journal of Biochemistry, 122(1), 122–128.

    Article  CAS  PubMed  Google Scholar 

  27. Zancan, P., et al. (2007). Fructose-2,6-bisphosphate counteracts guanidinium chloride-, thermal-, and ATP-induced dissociation of skeletal muscle key glycolytic enzyme 6-phosphofructo-1-kinase: A structural mechanism for PFK allosteric regulation. Archives of Biochemistry and Biophysics, 467(2), 275–282.

    Article  CAS  PubMed  Google Scholar 

  28. Zancan, P., et al. (2008). ATP and fructose-2,6-bisphosphate regulate skeletal muscle 6-phosphofructo-1-kinase by altering its quaternary structure. IUBMB Life, 60(8), 526–533.

    Article  CAS  PubMed  Google Scholar 

  29. Uyeda, K. (1979). Phosphofructokinase. Advances in Enzymology and Related Areas of Molecular Biology, 48, 193–244.

    CAS  PubMed  Google Scholar 

  30. Uyeda, K., Furuya, E., & Luby, L. J. (1981). The effect of natural and synthetic D-fructose 2,6-bisphosphate on the regulatory kinetic properties of liver and muscle phosphofructokinases. Journal of Biological Chemistry, 256(16), 8394–8399.

    Article  CAS  PubMed  Google Scholar 

  31. Costa Leite, T., et al. (2007). Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis. The Biochemical Journal, 408(1), 123–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Usenik, A., & Legiša, M. (2010). Evolution of allosteric citrate binding sites on 6-phosphofructo-1-kinase. PLoS One, 5(11), e15447.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jenkins, C. M., et al. (2011). Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: A mechanism integrating glycolytic flux with lipid metabolism. Journal of Biological Chemistry, 286(14), 11937–11950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yi, M., et al. (2019). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer. Molecular Metabolism, 20, 1–13.

    Article  PubMed  CAS  Google Scholar 

  35. Kim, S. G., et al. (2006). Crystal structure of the hypoxia-inducible form of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): A possible new target for cancer therapy. Journal of Biological Chemistry, 281(5), 2939–2944.

    Article  CAS  PubMed  Google Scholar 

  36. Manes, N. P., & El-Maghrabi, M. R. (2005). The kinase activity of human brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is regulated via inhibition by phosphoenolpyruvate. Archives of Biochemistry and Biophysics, 438(2), 125–136.

    Article  CAS  PubMed  Google Scholar 

  37. Kim, S. G., et al. (2007). A direct substrate-substrate interaction found in the kinase domain of the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Journal of Molecular Biology, 370(1), 14–26.

    Article  CAS  PubMed  Google Scholar 

  38. Navarro-Sabaté, A., et al. (2001). The human ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFB3): Promoter characterization and genomic structure. Gene, 264(1), 131–138.

    Article  PubMed  Google Scholar 

  39. Obach, M., et al. (2004). 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. Journal of Biological Chemistry, 279(51), 53562–53570.

    Article  CAS  PubMed  Google Scholar 

  40. Novellasdemunt, L., et al. (2012). Progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells. The Biochemical Journal, 442(2), 345–356.

    Article  CAS  PubMed  Google Scholar 

  41. Hamilton, J. A., et al. (1997). Identification of PRG1, a novel progestin-responsive gene with sequence homology to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Molecular Endocrinology, 11(4), 490–502.

    Article  CAS  PubMed  Google Scholar 

  42. Imbert-Fernandez, Y., et al. (2014). Estradiol stimulates glucose metabolism via 6-phosphofructo-2-kinase (PFKFB3). Journal of Biological Chemistry, 289(13), 9440–9448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen, L., et al. (2016). PFKFB3 Control of cancer growth by responding to Circadian clock outputs. Science and Reports, 6, 24324.

    Article  CAS  Google Scholar 

  44. Bartrons, R., & Caro, J. (2007). Hypoxia, glucose metabolism and the Warburg’s effect. Journal of Bioenergetics and Biomembranes, 39(3), 223–229.

    Article  CAS  PubMed  Google Scholar 

  45. Minchenko, A., et al. (2002). Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. Journal of Biological Chemistry, 277(8), 6183–7.

    Article  CAS  PubMed  Google Scholar 

  46. Fukasawa, M., et al. (2004). Identification and characterization of the hypoxia-responsive element of the human placental 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene. Journal of Biochemistry, 136(3), 273–277.

    Article  CAS  PubMed  Google Scholar 

  47. Novellasdemunt, L., et al. (2013). PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli. The Biochemical Journal, 452(3), 531–543.

    Article  CAS  PubMed  Google Scholar 

  48. Huangyang, P., & Simon, M. C. (2018). Hidden features: Exploring the non-canonical functions of metabolic enzymes. Disease Models & Mechanisms, 11(8).

  49. Yalcin, A., et al. (2009). Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases. Journal of Biological Chemistry, 284(36), 24223–24232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yalcin, A., et al. (2014). 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death and Disease, 5(7), e1337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jia, W., et al. (2018). Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4. Oncogene, 37(13), 1685–1698.

    Article  CAS  PubMed  Google Scholar 

  52. Gustafsson, N. M. S., et al. (2018). Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination. Nature Communications, 9(1), 3872.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Shi, W. K., et al. (2018). PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT. Cell Death & Disease, 9(4), 428.

    Article  CAS  Google Scholar 

  54. Atsumi, T., et al. (2002). High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Research, 62(20), 5881–5887.

    CAS  PubMed  Google Scholar 

  55. Minchenko, O., Opentanova, I., & Caro, J. (2003). Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family (PFKFB-1-4) expression in vivo. FEBS Letters, 554(3), 264–270.

    Article  CAS  PubMed  Google Scholar 

  56. Bartrons, R., et al. (2018). The potential utility of PFKFB3 as a therapeutic target. Expert Opinion on Therapeutic Targets, 22(8), 659–674.

    Article  CAS  PubMed  Google Scholar 

  57. Chesney, J. (2006). 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Current Opinion in Clinical Nutrition and Metabolic Care, 9(5), 535–539.

    Article  CAS  PubMed  Google Scholar 

  58. Peng, F., et al. (2018). PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis. International Journal of Oncology, 52(3), 945–954.

    CAS  PubMed  Google Scholar 

  59. Li, H. M., et al. (2017). Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma. Journal of Experimental & Clinical Cancer Research, 36(1), 7.

    Article  CAS  Google Scholar 

  60. Lin, S., et al. (2021). Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression. Cancer Letters, 518, 230–242.

    Article  CAS  PubMed  Google Scholar 

  61. Li, X., et al. (2018). Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy. Molecular and Cellular Biochemistry, 445(1–2), 123–134.

    Article  CAS  PubMed  Google Scholar 

  62. Minchenko, O. H., et al. (2005). Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie, 87(11), 1005–1010.

    Article  CAS  PubMed  Google Scholar 

  63. De Oliveira, T., et al. (2021). Effects of the novel PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and its systemic toxicity evaluation in vivo. Cancers (Basel), 13(5)

  64. Minchenko, O. H., et al. (2014). Mechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells. World Journal of Gastroenterology, 20(38), 13705–13717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kessler, R., et al. (2008). 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas. Journal of Neuro-oncology, 86(3), 257–264.

    Article  CAS  PubMed  Google Scholar 

  66. Deng, X., et al. (2019). ROCK2 promotes osteosarcoma growth and metastasis by modifying PFKFB3 ubiquitination and degradation. Experimental Cell Research, 385(2), 111689.

    Article  CAS  PubMed  Google Scholar 

  67. Cieslar-Pobuda, A., et al. (2015). The expression pattern of PFKFB3 enzyme distinguishes between induced-pluripotent stem cells and cancer stem cells. Oncotarget, 6(30), 29753–29770.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Pacini, N., & Borziani, F. (2014). Cancer stem cell theory and the Warburg effect, two sides of the same coin? International Journal of Molecular Sciences, 15(5), 8893–8930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shi, L., et al. (2017). Roles of PFKFB3 in cancer. Signal Transduction and Targeted Therapy, 2, 17044.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Yetkin-Arik, B., et al. (2019). The role of glycolysis and mitochondrial respiration in the formation and functioning of endothelial tip cells during angiogenesis. Science and Reports, 9(1), 12608.

    Article  CAS  Google Scholar 

  71. Schoors, S., et al. (2014). Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metabolism, 19(1), 37–48.

    Article  CAS  PubMed  Google Scholar 

  72. Xu, Y., et al. (2014). Endothelial PFKFB3 plays a critical role in angiogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(6), 1231–1239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cruys, B., et al. (2016). Glycolytic regulation of cell rearrangement in angiogenesis. Nature Communications, 7, 12240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. De Bock, K., et al. (2013). Role of PFKFB3-driven glycolysis in vessel sprouting. Cell, 154(3), 651–663.

    Article  PubMed  CAS  Google Scholar 

  75. Cantelmo, A. R., et al. (2016). Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell, 30(6), 968–985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Marsin, A. S., et al. (2002). The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. Journal of Biological Chemistry, 277(34), 30778–30783.

    Article  CAS  PubMed  Google Scholar 

  77. Bando, H., et al. (2005). Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clinical Cancer Research, 11(16), 5784–5792.

    Article  CAS  PubMed  Google Scholar 

  78. Lypova, N., et al. (2019). Increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 activity in response to EGFR signaling contributes to non-small cell lung cancer cell survival. Journal of Biological Chemistry, 294(27), 10530–10543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Domenech, E., et al. (2015). AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. Nature Cell Biology, 17(10), 1304–1316.

    Article  CAS  PubMed  Google Scholar 

  80. Xing, Z., et al. (2018). Expression of long noncoding RNA YIYA promotes glycolysis in breast cancer. Cancer Research, 78(16), 4524–4532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ma, H., et al. (2020). c-Src promotes tumorigenesis and tumor progression by activating PFKFB3. Cell Reports, 30(12), 4235-4249 e6.

    Article  CAS  PubMed  Google Scholar 

  82. Wang, F., et al. (2020). p38γ MAPK is essential for aerobic glycolysis and pancreatic tumorigenesis. Cancer Research, 80(16), 3251–3264.

    Article  CAS  PubMed  Google Scholar 

  83. Reid, M. A., et al. (2016). IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes & Development, 30(16), 1837–1851.

    Article  CAS  Google Scholar 

  84. Lei, Y., et al. (2020). O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia. Oncogenesis, 9(2), 21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, F. L., et al. (2018). Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis. Nature Communications, 9(1), 508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Yamamoto, T., et al. (2014). Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway. Nature Communications, 5, 3480.

    Article  PubMed  CAS  Google Scholar 

  87. Tudzarova, S., et al. (2011). Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle. Proc Natl Acad Sci U S A, 108(13), 5278–5283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Herrero-Mendez, A., et al. (2009). The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nature Cell Biology, 11(6), 747–752.

    Article  CAS  PubMed  Google Scholar 

  89. Desideri, E., et al. (2014). MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation. Autophagy, 10(9), 1652–1665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rodriguez-Rodriguez, P., et al. (2012). Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death and Differentiation, 19(10), 1582–1589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Liu, J., et al. (2020). Long noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming. Nature Communications, 11(1), 1507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liou, G. Y., & Storz, P. (2010). Reactive oxygen species in cancer. Free Radical Research, 44(5), 479–496.

    Article  CAS  PubMed  Google Scholar 

  93. Robinson, A. J., et al. (2020). Reactive oxygen species drive proliferation in acute myeloid leukemia via the glycolytic regulator PFKFB3. Cancer Research, 80(5), 937–949.

    Article  CAS  PubMed  Google Scholar 

  94. Yang, Z., et al. (2013). Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. Journal of Experimental Medicine, 210(10), 2119–2134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. GhanbariMovahed, Z., et al. (2019). Cancer cells change their glucose metabolism to overcome increased ROS: One step from cancer cell to cancer stem cell? Biomedicine & Pharmacotherapy, 112, 108690.

    Article  CAS  Google Scholar 

  96. Seo, M., & Lee, Y. H. (2014). PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer. Journal of Molecular Biology, 426(4), 830–842.

    Article  CAS  PubMed  Google Scholar 

  97. Wang, Y., et al. (2020). PFKFB3 inhibitors as potential anticancer agents: Mechanisms of action, current developments, and structure-activity relationships. European Journal of Medicinal Chemistry, 203, 112612.

    Article  CAS  PubMed  Google Scholar 

  98. Clem, B., et al. (2008). Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Molecular Cancer Therapeutics, 7(1), 110–120.

    Article  CAS  PubMed  Google Scholar 

  99. Pisarsky, L., et al. (2016). Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Reports, 15(6), 1161–1174.

    Article  CAS  PubMed  Google Scholar 

  100. Xintaropoulou, C., et al. (2015). A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models. Oncotarget, 6(28), 25677–25695.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Xintaropoulou, C., et al. (2018). Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment. BMC Cancer, 18(1), 636.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Lea, M. A., Altayyar, M., & Desbordes, C. (2015). Inhibition of growth of bladder cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one in combination with other compounds affecting glucose metabolism. Anticancer Research, 35(11), 5889–99.

    CAS  PubMed  Google Scholar 

  103. Houddane, A., et al. (2017). Role of Akt/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes. Cellular Signalling, 34, 23–37.

    Article  CAS  PubMed  Google Scholar 

  104. Clem, B. F., et al. (2013). Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Molecular Cancer Therapeutics, 12(8), 1461–1470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhu, W., et al. (2016). PFK15, a small molecule inhibitor of PFKFB3, induces cell cycle arrest, apoptosis and inhibits invasion in gastric cancer. PLoS One, 11(9), e0163768.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Horváthová, J., et al. (2021). Inhibition of glycolysis suppresses cell proliferation and tumor progression in vivo: Perspectives for chronotherapy. International Journal of Molecular Sciences, 22(9)

  107. Feng, Y., & Wu, L. (2017). mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival. Biochemical and Biophysical Research Communications, 483(2), 897–903.

    Article  CAS  PubMed  Google Scholar 

  108. Matsumoto, K., et al. (2021). Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel normalization in hepatocellular carcinoma. Cancer Letters, 500, 29–40.

    Article  CAS  PubMed  Google Scholar 

  109. Wang, C., et al. (2018). PFK15, a PFKFB3 antagonist, inhibits autophagy and proliferation in rhabdomyosarcoma cells. International Journal of Molecular Medicine, 42(1), 359–367.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Liu, X., et al., The synergistic effect of PFK15 with metformin exerts anti-myeloma activity via PFKFB3. Biochem Biophys Res Commun, 2019.

  111. Redman, R., et al., PFK-158, first-in-man and first-in-class inhibitor of PFKFB3/ glycolysis: A phase I, dose escalation, multi-center study in patients with advanced solid malignancies. 2015, Cancer Res: AACR.

  112. Telang, S., et al., PFK-158 is a first-in-human inhibitor of PFKFB3 that selectively suppresses glucose metabolism of cancer cells and inhibits the immunosuppressive Th17 cells and MDSCs in advanced cancer patients. 2016: Cancer Res.

  113. Xiao, Y., et al. (2021). Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer. Oncogene, 40(8), 1409–1424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mondal, S., et al. (2019). Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. International Journal of Cancer, 144(1), 178–189.

    Article  CAS  PubMed  Google Scholar 

  115. Lea, M. A., Guzman, Y., & Desbordes, C. (2016). Inhibition of growth by combined treatment with inhibitors of lactate dehydrogenase and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3. Anticancer Research, 36(4), 1479–1488.

    CAS  PubMed  Google Scholar 

  116. Boyd, S., et al. (2015). Structure-based design of potent and selective inhibitors of the metabolic kinase PFKFB3. Journal of Medicinal Chemistry, 58(8), 3611–3625.

    Article  CAS  PubMed  Google Scholar 

  117. Zheng, X., et al. (2017). LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism. EMBO Journal, 36(22), 3325–3335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Burmistrova, O., et al. (2019). Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice. Science and Reports, 9(1), 11670.

    Article  CAS  Google Scholar 

  119. Oliveira, T., et al. (2021). Effects of the novel PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and its systemic toxicity evaluation in vivo. Cancers (Basel), 13(5)

  120. Seo, M., et al. (2011). Structure-based development of small molecule PFKFB3 inhibitors: A framework for potential cancer therapeutic agents targeting the Warburg effect. PLoS One, 6(9), e24179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Harada, Y., et al. (1997). Inhibition of fructose-6-phosphate,2-kinase by N-bromoacetylethanolamine phosphate in vitro and in vivo. Journal of Biochemistry, 121(4), 724–730.

    Article  CAS  PubMed  Google Scholar 

  122. Brooke, D. G., et al. (2014). Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Bioorganic & Medicinal Chemistry, 22(3), 1029–1039.

    Article  CAS  Google Scholar 

  123. St-Gallay, S. A., et al. (2018). A high-throughput screening triage workflow to authenticate a novel series of PFKFB3 inhibitors. SLAS Discov, 23(1), 11–22.

    Article  CAS  PubMed  Google Scholar 

  124. Boutard, N., et al. (2019). Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties. Bioorganic & Medicinal Chemistry Letters, 29(4), 646–653.

    Article  CAS  Google Scholar 

  125. Macut, H., et al. (2019). Tuning PFKFB3 bisphosphatase activity through allosteric interference. Science and Reports, 9(1), 20333.

    Article  CAS  Google Scholar 

  126. Kotowski, K., et al. (2021). Role of PFKFB3 and PFKFB4 in cancer: Genetic basis, impact on disease development/progression, and potential as therapeutic targets. Cancers (Basel), 13(4)

  127. Zhu, Y., et al. (2018). Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor. Oncogene, 37(21), 2837–2849.

    Article  CAS  PubMed  Google Scholar 

  128. Atsumi, T., et al. (2005). Expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase/PFKFB3 isoforms in adipocytes and their potential role in glycolytic regulation. Diabetes, 54(12), 3349–3357.

    Article  CAS  PubMed  Google Scholar 

  129. Fu, W., et al. (2015). Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity. Journal of Biological Chemistry, 290(20), 12504–12513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Emini Veseli, B., et al. (2020). Small molecule 3PO inhibits glycolysis but does not bind to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). FEBS Letters, 594(18), 3067–3075.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Department of Defense Breast Cancer Research Program (CA171885) and from the National Cancer Institute (U01CA184902) and The Hormel Foundation to Dr. Clarke.

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Authors and Affiliations

  1. Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA

    Brandon C. Jones

  2. Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, TX, 77030, USA

    Paula R. Pohlmann

  3. The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA

    Robert Clarke & Surojeet Sengupta

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  1. Brandon C. Jones
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Correspondence to Surojeet Sengupta.

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Jones, B.C., Pohlmann, P.R., Clarke, R. et al. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux. Cancer Metastasis Rev 41, 447–458 (2022). https://doi.org/10.1007/s10555-022-10027-5

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