The regulatory roles and clinical significance of glycolysis in tumor

Abstract

Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells, among which glycolysis is an important form. Recent research has revealed that the heightened glycolysis levels, the abnormal expression of glycolytic enzymes, and the accumulation of glycolytic products could regulate the growth, proliferation, invasion, and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression. Based on the distinctive glycolytic characteristics of tumor cells, novel imaging tests have been developed to evaluate tumor proliferation and metastasis. In addition, glycolytic enzymes have been found to serve as promising biomarkers in tumor, which could provide assistance in the early diagnosis and prognostic assessment of tumor patients. Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment, and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic. In this review, we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.

Keywords

glycolysis / tumor development / biomarkers / targeted therapy

References

[1] Li L, Wang M, Ma Q, Ye J, Sun G. Role of glycolysis in the development of atherosclerosis. Am J Physiol Cell Physiol. 2022; 323(2): C617-C29.

[2] Bell SM, Burgess T, Lee J, Blackburn DJ, Allen SP, Mortiboys H. Peripheral Glycolysis in Neurodegenerative Diseases. Int J Mol Sci. 2020; 21(23): 8924.

[3] Bustamante MF, Oliveira PG, Garcia-Carbonell R. Croft AP, Smith JM, Serrano RL, et al. Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis. Ann Rheum Dis. 2018; 77(11): 1636-43.

[4] Chang SM, Vander Heiden MG. Inhibiting GLUTtony in cancer. Cell Chem Biol. 2022; 29(3): 353-5.

[5] Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008; 134(5): 703-7.

[6] Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. 2013; 24(2): 213-28.

[7] Xiang J, Hu Q, Qin Y, Ji S, Xu W, Liu W, et al. TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1alpha axis and indicates prognosis in pancreatic cancer. Cell Death Dis. 2018; 9(3): 321.

[8] Lopez-Lazaro M. The warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem. 2008; 8(3): 305-12.

[9] Vaupel P, Schmidberger H, Mayer A. The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol. 2019; 95(7): 912-9.

[10] He H, Xiao L, Wang J, Guo D, Lu Z. Aerobic glycolysis promotes tumor immune evasion and tumor cell stemness through the noncanonical function of hexokinase 2. Cancer Commun (Lond). 2023; 43(3): 387-90.

[11] Gatenby RA, Gawlinski ET. The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. Cancer Res. 2003; 63(14): 3847-54.

[12] Li Y, Li Y, Luo J, Fu X, Liu P, Liu S, et al. FAM126A hainteracted with ENO1 mediates proliferation and metastasis in pancreatic cancer via PI3K/AKT signaling pathway. Cell Death Discov. 2022; 8(1): 248.

[13] Wang G, Zheng H, Xiang Y, Wang Y, Wang K, Ren X, et al. Identifying the critical oncogenic mechanism of LDHA based on a prognostic model of T-cell synthetic drivers. Int Immunopharmacol. 2024; 126: 111265.

[14] Lin X, Xiao Z, Chen T, Liang SH, Guo H. Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment. Front Oncol. 2020; 10: 317.

[15] Enzo E, Santinon G, Pocaterra A, Aragona M, Bresolin S, Forcato M, et al. Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J. 2015; 34(10): 1349-70.

[16] Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014; 15(6): 122.

[17] Ohba S, Tang Y, Johannessen TA, Mukherjee J. PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas. Front Oncol. 2022; 12: 844861.

[18] Zhang R, Shen M, Wu C, Chen Y, Lu J, Li J, et al. HDAC8-dependent deacetylation of PKM2 directs nuclear localization and glycolysis to promote proliferation in hepatocellular carcinoma. Cell Death Dis. 2020; 11(12): 1036.

[19] Fu H, Gao H, Qi X, Zhao L, Wu D, Bai Y, et al. Aldolase A promotes proliferation and G(1)/S transition via the EGFR/MAPK pathway in non-small cell lung cancer. Cancer Commun (Lond). 2018; 38(1): 18.

[20] Li S, Li J, Dai W, Zhang Q, Feng J, Wu L, et al. Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death. Br J Cancer. 2017; 117(10): 1518-28.

[21] Afonso J, Goncalves C, Costa M, Ferreira D, Santos L, Longatto-Filho A. et al. Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy. Cancers (Basel). 2023; 15(3): 982.

[22] Yalcin A, Clem BF, Simmons A, Lane A, Nelson K, Clem AL, et al. Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases. J Biol Chem. 2009; 284(36): 24223-32.

[23] Calvo MN, Bartrons R, Castano E, Perales JC, Navarro-Sabate A. Manzano A. PFKFB3 gene silencing decreases glycolysis, induces cell-cycl. delay and inhibits anchorage-independent growth in HeLa cells. FEBS Lett. 2006; 580(13): 3308-14.

[24] Li J, Zhang S, Liao D, Zhang Q, Chen C, Yang X, et al. Overexpression of PFKFB3 promotes cell glycolysis and proliferation in renal cell carcinoma. BMC Cancer. 2022; 22(1): 83.

[25] Matsumoto K, Noda T, Kobayashi S, Sakano Y, Yokota Y, Iwagami Y, et al. Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel normalization in hepatocellular carcinoma. Cancer Lett. 2021;500: 29-640.

[26] Mamczur P, Gamian A, Kolodziej J, Dziegiel P, Rakus D. Nuclear localization of aldolase A correlates with cell proliferation. Biochim Biophys Acta. 2013; 1833(12): 2812-22.

[27] Rose IA, O’Connell EL. Studies on the interaction of aldolase with substrate analogues. J Biol Chem. 1969; 244(1): 126-34.

[28] Zhou J, Lei N, Qin B, Chen M, Gong S, Sun H, et al. Aldolase A promotes cervical cancer cell radioresistance by regulating the glycolysis and DNA damage after irradiation. Cancer Biol Ther. 2023; 24(1): 2287128.

[29] Sundararaj KP, Wood RE, Ponnusamy S, Salas AM, Szulc Z, Bielawska A, et al. Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem. 2004; 279(7): 6152-62.

[30] Li T, Tan X, Yang R, Miao Y, Zhang M, Xi Y, et al. Discovery of novel glyceraldehyde-3-phosphate dehydrogenase inhibitor via docking-based virtual screening. Bioorg Chem. 2020; 96: 103620.

[31] Joseph J, Cruz-Sanchez FF. Carreras J. Enolase activity and isoenzyme distribution in human brain regions and tumors. J Neurochem. 1996; 66(6): 2484-90.

[32] Zhang J, Li H, Miao L, Ding J. Silencing of ENO1 inhibits the proliferation, migration and invasion of human breast cancer cells. J BUON. 2020; 25(2): 696-701.

[33] Liu Y, Liao L, An C, Wang X, Li Z, Xu Z, et al. alpha-Enolase Lies Downstream of mTOR/HIF1alpha and Promotes Thyroid Carcinoma Progression by Regulating CST1. Front Cell Dev Biol. 2021; 9: 670019.

[34] Qiao H, Wang Y, Zhu B, Jiang L, Yuan W, Zhou Y, et al. Enolase1 overexpression regulates the growth of gastric cancer cells and predicts poor survival. J Cell Biochem. 2019; 120(11): 18714-23.

[35] Xia Y, Wang X, Liu Y, Shapiro E, Lepor H, Tang MS, et al. PKM2 Is Essential for Bladder Cancer Growth and Maintenance. Cancer Res. 2022; 82(4): 571-85.

[36] Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell. 2013; 52(3): 340-52.

[37] Yang W, Lu Z. Nuclear PKM2 regulates the Warburg effect. Cell Cycle. 2013; 12(19): 3154-8.

[38] Wu Z, Wu J, Zhao Q, Fu S, Jin J. Emerging roles of aerobic glycolysis in breast cancer. Clin Transl Oncol. 2020; 22(5): 631-46.

[39] Yuan Q, Yu H, Chen J, Song X, Sun L. Knockdown of pyruvate kinase type M2 suppresses tumor survival and invasion in osteosarcoma cells both in vitro and in vivo. Exp Cell Res. 2018; 362(1): 209-16.

[40] Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature. 2011; 480(7375): 118-22.

[41] Lin Y, Wang Y, Li PF. Mutual regulation of lactate dehydrogenase and redox robustness. Front Physiol. 2022; 13: 1038421.

[42] Serganova I, Cohen IJ, Vemuri K, Shindo M, Maeda M, Mane M, et al. LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response. PLoS One. 2018; 13(9): e0203965.

[43] Muramatsu H, Sumitomo M, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, et al. Targeting lactate dehydrogenase A promotes docetaxel induced cytotoxicity predominantly in castration resistant prostate cancer cells. Oncol Rep. 2019; 42(1): 224-30.

[44] Harada K, Oita E, Chiba K. Metaphase I arrest of starfish oocytes induced via the MAP kinase pathway is released by an increase of intracellular pH. Development. 2003; 130(19): 4581-6.

[45] Epstein T, Xu L, Gillies RJ, Gatenby RA. Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane. Cancer Metab. 2014; 2: 7.

[46] Li Z, Yang P, Li Z. The multifaceted regulation and functions of PKM2 in tumor progression. Biochim Biophys Acta. 2014; 1846(2): 285-96.

[47] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646-74.

[48] Verdegem D, Moens S, Stapor P, Carmeliet P. Endothelial cell metabolism: parallels and divergences with cancer cell metabolism. Cancer Metab. 2014; 2: 19.

[49] Yang J, Ren B, Yang G, Wang H, Chen G, You L, et al. The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol Life Sci. 2020; 77(2): 305-21.

[50] Wang G, Su H, Guo Z, Li H, Jiang Z, Cao Y, et al. Rubus Occidentalis and its bioactive compounds against cancer: From molecular mechanisms to translational advances. Phytomedicine. 2024; 126: 155029.

[51] Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011; 71(7): 2550-60.

[52] Li L, Zhang Y, Qiao J, Yang JJ, Liu ZR. Pyruvate kinase M2 in blood circulation facilitates tumor growth by promoting angiogenesis. J Biol Chem. 2014; 289(37): 25812-21.

[53] Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. Mol Cancer. 2016; 15: 3.

[54] Peng F, Li Q, Sun JY, Luo Y, Chen M, Bao Y. PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis. Int J Oncol. 2018; 52(3): 945-54.

[55] Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene. 2001; 20(28): 3751-6.

[56] Jung SY, Song HS, Park SY, Chung SH, Kim YJ. Pyruvate promotes tumor angiogenesis through HIF-1-dependent PAI-1 expression. Int J Oncol. 2011; 38(2): 571-6.

[57] Yang P, Li Z, Wang Y, Zhang L, Wu H, Li Z. Secreted pyruvate kinase M2 facilitates cell migration via PI3K/Akt and Wnt/beta-catenin pathway in colon cancer cells. Biochem Biophys Res Commun. 2015; 459(2): 327-32.

[58] Yang X, Li W, Han X, Wang J, Dai J, Ye X, et al. Apatinib weakens proliferation, migration, invasion, and angiogenesis of thyroid cancer cells through downregulating pyruvate kinase M2. Sci Rep. 2024; 14(1): 879.

[59] Gao J, Zhao R, Xue Y, Niu Z, Cui K, Yu F, et al. Role of enolase-1 in response to hypoxia in breast cancer: exploring the mechanisms of action. Oncol Rep. 2013; 29(4): 1322-32.

[60] Abou Khouzam R, Zaarour RF, Brodaczewska K, Azakir B, Venkatesh GH, Thiery J, et al. The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes? Front Immunol. 2022; 13: 828875.

[61] Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007; 109(9): 3812-9.

[62] Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer. 2012; 131(3): 633-40.

[63] Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513(7519): 559-63.

[64] Urata K, Kajihara I, Miyauchi H, Mijiddorj T, Otsuka-Maeda S. Sakamoto R, et al. The Warburg effect and tumour immune microenvironment in extramammary Paget’s disease: overexpression of lactate dehydrogenase A correlates with immune resistance. J Eur Acad Dermatol Venereol. 2020; 34(8): 1715-21.

[65] Ohashi T, Aoki M, Tomita H, Akazawa T, Sato K, Kuze B, et al. M2-like macrophage polarization in high lactic acid-producing head and neck cancer. Cancer Sci. 2017; 108(6): 1128-34.

[66] Gottfried E, Kunz-Schughart LA. Ebner S, Mueller-Klieser W. Hoves S, Andreesen R, et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006; 107(5): 2013-21.

[67] Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016; 24(5): 657-71.

[68] Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol. 2010; 184(3): 1200-9.

[69] De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. 2015; 16(11): 1174-84.

[70] Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of T(reg) stability in glycolysis-low tumours. Nature. 2021; 591(7851): 652-8.

[71] Curi R, Levada-Pires AC. Silva EBD, Poma SO, Zambonatto RF, Domenech P, et al. The Critical Role of Cell Metabolism for Essential Neutrophil Functions. Cell Physiol Biochem. 2020; 54(4): 629-47.

[72] Leifler KS, Svensson S, Abrahamsson A, Bendrik C, Robertson J, Gauldie J, et al. Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer. J Immunol. 2013; 190(8): 4420-30.

[73] Wang J, Wang X, Guo Y, Ye L, Li D, Hu A, et al. Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancer cells and neutrophils inhibits aerobic glycolysis and cancer progression. Clin Transl Med. 2021; 11(11): e588.

[74] Wang L, Liu Y, Dai Y, Tang X, Yin T, Wang C, et al. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. Gut. 2023; 72(5): 958-71.

[75] Deng H, Kan A, Lyu N, He M, Huang X, Qiao S, et al. Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma. J Immunother Cancer. 2021; 9(6): e002305.

[76] Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE. Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591(7851): 645-51.

[77] Principe M, Borgoni S, Cascione M, Chattaragada MS, Ferri-Borgogno S. Capello M, et al. Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis. J Hematol Oncol. 2017; 10(1): 16.

[78] Li J, Wang F, Gao H, Huang S, Cai F, Sun J. ALDOLASE A regulates invasion of bladder cancer cells via E-cadherin-EGFR signaling. J Cell Biochem. 2019; 120(8): 13694-705.

[79] Nikoobakht M, Shamshiripour P, Azimi Nekoo Z, Fallah Haghmohammadi S. Elevated Lactate and Total Protein Levels in Stereotactic Brain Biopsy Specimen; Potential Biomarkers of Malignancy and Poor Prognosis. Arch Iran Med. 2019; 22(3): 125-31.

[80] Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001; 51(2): 349-53.

[81] Zhan P, Zhao S, Yan H, Yin C, Xiao Y, Wang Y, et al. alpha-enolase promotes tumorigenesis and metastasis via regulating AMPK/mTOR pathway in colorectal cancer. Mol Carcinog. 2017; 56(5): 1427-37.

[82] Hsiao KC, Shih NY, Fang HL, Huang TS, Kuo CC, Chu PY, et al. Surface alpha-enolase promotes extracellular matrix degradation and tumor metastasis and represents a new therapeutic target. PLoS One. 2013; 8(7): e69354.

[83] Kumari S, Malla R. New Insight on the Role of Plasminogen Receptor in Cancer Progression. Cancer Growth Metastasis. 2015; 8: 35-42.

[84] Trojanowicz B, Winkler A, Hammje K, Chen Z, Sekulla C, Glanz D, et al. Retinoic acid-mediated down-regulation of ENO1/MBP-1 gene products caused decreased invasiveness of the follicular thyroid carcinoma cell lines. J Mol Endocrinol. 2009; 42(3): 249-60.

[85] Cui J, Shi M, Xie D, Wei D, Jia Z, Zheng S, et al. FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clin Cancer Res. 2014; 20(10): 2595-606.

[86] Hua S, Lei L, Deng L, Weng X, Liu C, Qi X, et al. miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1. Oncogene. 2018; 37(12): 1624-36.

[87] Yang K, Zhong Z, Zou J, Liao JY, Chen S, Zhou S, et al. Glycolysis and tumor progression promoted by the m(6)A writer VIRMA via m(6)A-dependent upregulation of STRA6 in pancreatic ductal adenocarcinoma. Cancer Lett. 2024; 590: 216840.

[88] Li S, Dai W, Mo W, Li J, Feng J, Wu L, et al. By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma. Int J Cancer. 2017; 141(12): 2571-84.

[89] Li Y, Lu Z, Liang Z, Ji D, Zhang P, Liu Q, et al. Metastasis-associated in colon cancer-1 is associated with poor prognosis in hepatocellular carcinoma, partly by promoting proliferation through enhanced glucose metabolism. Mol Med Rep. 2015; 12(1): 426-34.

[90] Saito Y, Takasawa A, Takasawa K, Aoyama T, Akimoto T, Ota M, et al. Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma. Cancer Sci. 2020; 111(8): 3071-81.

[91] Zhang Y, Cai H, Liao Y, Zhu Y, Wang F, Hou J. Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell like properties and the epithelial mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway. Int J Oncol. 2020; 57(3): 743-55.

[92] Sun L, Lu T, Tian K, Zhou D, Yuan J, Wang X, et al. Alpha-enolase promotes gastric cancer cell proliferation and metastasis via regulating AKT signaling pathway. Eur J Pharmacol. 2019; 845: 8-15.

[93] Lu J, Kornmann M, Traub B. Role of Epithelial to Mesenchymal Transition in Colorectal Cancer. Int J Mol Sci. 2023; 24(19): 14815.

[94] Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019; 20(2): 69-84.

[95] Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov. 2016; 15(5): 311-25.

[96] Ji S, Zhang B, Liu J, Qin Y, Liang C, Shi S, et al. ALDOA functions as an oncogene in the highly metastatic pancreatic cancer. Cancer Lett. 2016; 374(1): 127-35.

[97] Lin Y, Zhang W, Liu L, Li W, Li Y, Li B. ENO1 Promotes OSCC Migration and Invasion by Orchestrating IL-6 Secretion from Macrophages via a Positive Feedback Loop. Int J Mol Sci. 2023; 24(1): 737.

[98] Li HJ, Ke FY, Lin CC, Lu MY, Kuo YH, Wang YP, et al. ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling-Driven Epithelial-to-Mesenchymal Transition. Cancer Res. 2021; 81(15): 4094-109.

[99] Yang P, Li Z, Fu R, Wu H, Li Z. Pyruvate kinase M2 facilitates colon cancer cell migration via the modulation of STAT3 signalling. Cell Signal. 2014; 26(9): 1853-62.

[100] Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. 2013; 34(2-3): 121-38.

[101] Stringer DM, Zahradka P, Taylor CG. Glucose transporters: cellular links to hyperglycemia in insulin resistance and diabetes. Nutr Rev. 2015; 73(3): 140-54.

[102] Bao YY, Zhong JT, Shen LF, Dai LB, Zhou SH, Fan J, et al. Effect of Glut-1 and HIF-1alpha double knockout by CRISPR/CAS9 on radiosensitivity in laryngeal carcinoma via the PI3K/Akt/mTOR pathway. J Cell Mol Med. 2022; 26(10): 2881-94.

[103] Sharma V, Singh TG, Mannan A. Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia. Neurochem Res. 2022; 47(8): 2173-86.

[104] Barron CC, Bilan PJ, Tsakiridis T, Tsiani E. Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism. 2016; 65(2): 124-39.

[105] Gonzalez-Menendez P, Hevia D, Mayo JC, Sainz RM. The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas? Int J Cancer. 2018; 142(12): 2414-24.

[106] Shen N, Wang Y, Sun X, Bai X, He J, Cui Q, et al. Expression of hypoxia-inducible factor 1alpha, glucose transporter 1, and hexokinase 2 in primary central nervous system lymphoma and the correlation with the biological behaviors. Brain Behav. 2020; 10(8): e01718.

[107] Song MY, Lee DY, Yun SM, Kim EH. GLUT3 Promotes Epithelial-Mesenchymal Transition via TGF-beta/JNK/ATF2 Signaling Pathway in Colorectal Cancer Cells. Biomedicines. 2022; 10(8): 1837.

[108] Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013; 14(12): 759-74.

[109] Yim WW, Mizushima N. Lysosome biology in autophagy. Cell Discov. 2020; 6: 6.

[110] Cheong H. Integrating autophagy and metabolism in cancer. Arch Pharm Res. 2015; 38(3): 358-71.

[111] Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011; 10(9): 1533-41.

[112] Guo JY, Teng X, Laddha SV, Ma S, Van Nostrand SC, Yang Y, et al. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 2016; 30(15): 1704-17.

[113] Marcucci F, Rumio C. Tumor Cell Glycolysis-At the Crossroad of Epithelial-Mesenchymal Transition and Autophagy. Cells. 2022; 11(6): 1041.

[114] Qian X, Li X, Lu Z. Protein kinase activity of the glycolytic enzyme PGK1 regulates autophagy to promote tumorigenesis. Autophagy. 2017; 13(7): 1246-7.

[115] Soltany-Rezaee-Rad M, Mottaghi-Dastjerdi N. Setayesh N, Roshandel G, Ebrahimifard F, Sepehrizadeh Z. Overexpression of FOXO3, MYD88, and GAPDH Identified by Suppression Subtractive Hybridization in Esophageal Cancer Is Associated with Autophagy. Gastroenterol Res Pract. 2014; 2014: 185035.

[116] Zhang XY, Zhang M, Cong Q, Zhang MX, Zhang MY, Lu YY, et al. Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy. Int J Biochem Cell Biol. 2018; 95: 9-16.

[117] Ikeda S, Abe F, Matsuda Y, Kitadate A, Takahashi N, Tagawa H. Hypoxia-inducible hexokinase-2 enhances anti-apoptotic function via activating autophagy in multiple myeloma. Cancer Sci. 2020; 111(11): 4088-101.

[118] Bertin S, Samson M, Pons C, Guigonis JM, Gavelli A, Baque P, et al. Comparative proteomics study reveals that bacterial CpG motifs induce tumor cell autophagy in vitro and in vivo. Mol Cell Proteomics. 2008; 7(12): 2311-22.

[119] Wang L, Yang L, Yang Z, Tang Y, Tao Y, Zhan Q, et al. Glycolytic Enzyme PKM2 Mediates Autophagic Activation to Promote Cell Survival in NPM1-Mutated Leukemia. Int J Biol Sci. 2019; 15(4): 882-94.

[120] Yan S, Zhou N, Zhang D, Zhang K, Zheng W, Bao Y, et al. PFKFB3 Inhibition Attenuates Oxaliplatin-Induced Autophagy and Enhances Its Cytotoxicity in Colon Cancer Cells. Int J Mol Sci. 2019; 20(21): 5415.

[121] Das CK, Parekh A, Parida PK, Bhutia SK, Mandal M. Lactate dehydrogenase A regulates autophagy and tamoxifen resistance in breast cancer. Biochim Biophys Acta Mol Cell Res. 2019; 1866(6): 1004-18.

[122] Corbet C, Feron O. Tumour acidosis: from the passenger to the driver’s seat. Nat Rev Cancer. 2017; 17(10): 577-93.

[123] Li C, Wang S, Li C, Yin Y, Feng F, Fu H, et al. Improved risk stratification by PET-based intratumor heterogeneity in children with high-risk neuroblastoma. Front Oncol. 2022; 12: 896593.

[124] Gill R, Abdah-Bortnyak R. Amit A, Bar-Peled U. Keidar Z. [F18]FDG PET/CT-Derived Metabolic and Volumetric Biomarkers Can Predict Response to Treatment in Locally Advanced Cervical Cancer Patients. Cancers (Basel). 2022; 14(18): 4382.

[125] Jin P, Bai M, Liu J, Yu J, Meng X. Tumor metabolic and secondary lymphoid organ metabolic markers on 18F-fludeoxyglucose positron emission tomography predict prognosis of immune checkpoint inhibitors in advanced lung cancer. Front Immunol. 2022; 13: 1004351.

[126] Schmidt KC, Lucignani G, Sokoloff L. Fluorine-18-fluorodeoxyglucose PET to determine regional cerebral glucose utilization: a re-examination. J Nucl Med. 1996; 37(2): 394-9.

[127] Zhou H, Luby-Phelps K. Mickey BE, Habib AA, Mason RP, Zhao D. Dynamic near-infrared optical imaging of 2-deoxyglucose uptake by intracranial glioma of athymic mice. PLoS One. 2009; 4(11): e8051.

[128] Truszkiewicz A, Bartusik-Aebisher D. Zalejska-Fiolka J, Kawczyk-Krupka A. Aebisher D. Cellular Lactate Spectroscopy Using 1.5 Tesla Clinical Apparatus. Int J Mol Sci. 2022; 23(19): 11355.

[129] Serrao EM, Kettunen MI, Rodrigues TB, Dzien P, Wright AJ, Gopinathan A, et al. MRI with hyperpolarised [1-13C]pyruvate detects advanced pancreatic preneoplasia prior to invasive disease in a mouse model. Gut. 2016; 65(3): 465-75.

[130] Papanagiotou P, Backens M, Grunwald IQ, Farmakis G, Politi M, Roth C, et al. [MR spectroscopy in brain tumors]. Radiologe. 2007; 47(6): 520-9.

[131] Ross B, Helsper JT, Cox IJ, Young IR, Kempf R, Makepeace A, et al. Osteosarcoma and other neoplasms of bone. Magnetic resonance spectroscopy to monitor therapy. Arch Surg. 1987; 122(12): 1464-9.

[132] Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PE, Harzstark AL, Ferrone M, et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-(1)(3)C]pyruvate. Sci Transl Med. 2013; 5(198): 198ra08.

[133] Bharti SK, Shannon BA, Sharma RK, Levin AS, Morris CD, Bhujwalla ZM, et al. Characterization of lipomatous tumors with high-resolution (1)H MRS at 17.6T: Do benign lipomas, atypical lipomatous tumors and liposarcomas have a distinct metabolic signature? Front Oncol. 2022; 12: 920560.

[134] Tien RD, Lai PH, Smith JS, Lazeyras F. Single-voxel proton brain spectroscopy exam (PROBE/SV) in patients with primary brain tumors. AJR Am J Roentgenol. 1996; 167(1): 201-9.

[135] Zakian KL, Shukla-Dave A. Meyers P, Gorlick R, Healey J, Thaler HT, et al. Identification of prognostic markers in bone sarcomas using proton-decoupled phosphorus magnetic resonance spectroscopy. Cancer Res. 2003; 63(24): 9042-7.

[136] Chung-Faye G, Hayee B, Maestranzi S, Donaldson N, Forgacs I, Sherwood R. Fecal M2-pyruvate kinase (M2-PK): a novel marker of intestinal inflammation. Inflamm Bowel Dis. 2007; 13(11): 1374-8.

[137] Huang C, Huang Z, Bai P, Luo G, Zhao X, Wang X. Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis. Onco Targets Ther. 2018; 11: 2075-82.

[138] Liu W, Woolbright BL, Pirani K, Didde R, Abbott E, Kaushik G, et al. Tumor M2-PK: A novel urine marker of bladder cancer. PLoS One. 2019; 14(6): e0218737.

[139] Papadaki C, Sfakianaki M, Lagoudaki E, Giagkas G, Ioannidis G, Trypaki M, et al. PKM2 as a biomarker for chemosensitivity to front-line platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer. Br J Cancer. 2014; 111(9): 1757-64.

[140] Yu M, Yongzhi H, Chen S, Luo X, Lin Y, Zhou Y, et al. The prognostic value of GLUT1 in cancers: a systematic review and meta-analysis. Oncotarget. 2017; 8(26): 43356-67.

[141] Kim TH, Kwak Y, Song C, Lee HS, Kim DW, Oh HK, et al. GLUT-1 may predict metastases and death in patients with locally advanced rectal cancer. Front Oncol. 2023; 13: 1094480.

[142] Ma Y, Hu M, Zhou L, Ling S, Li Y, Kong B, et al. Long non-coding RNA HOTAIR promotes cancer cell energy metabolism in pancreatic adenocarcinoma by upregulating hexokinase-2. Oncol Lett. 2019; 18(3): 2212-9.

[143] Wu J, Hu L, Wu F, Zou L, He T. Poor prognosis of hexokinase 2 overexpression in solid tumors of digestive system: a meta-analysis. Oncotarget. 2017; 8(19): 32332-44.

[144] Liu D, Wang D, Wu C, Zhang L, Mei Q, Hu G, et al. Prognostic significance of serum lactate dehydrogenase in patients with breast cancer: a meta-analysis. Cancer Manag Res. 2019; 11: 3611-9.

[145] Ulas A, Turkoz FP, Silay K, Tokluoglu S, Avci N, Oksuzoglu B, et al. A laboratory prognostic index model for patients with advanced non-small cell lung cancer. PLoS One. 2014; 9(12): e114471.

[146] Li X, Liu J, Qian L, Ke H, Yao C, Tian W, et al. Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy. Mol Cell Biochem. 2018; 445(1-2): 123-34.

[147] Zhang L, Wang H, Dong X. Diagnostic value of alpha-enolase expression and serum alpha-enolase autoantibody levels in lung cancer. J Bras Pneumol. 2018; 44(1): 18-23.

[148] Lu W, Gao J, Yang J, Cao Y, Jiang L, Li M, et al. Down-Regulated Phosphoglycerate Kinase 1 Expression Is Associated With Poor Prognosis in Patients With Gallbladder Cancer. Medicine (Baltimore). 2015; 94(49): e2244.

[149] Vlachostergios PJ, Oikonomou KG, Gibilaro E, Apergis G. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark. 2015; 15(6): 725-34.

[150] Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA. Mueller-Klieser W. Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol. 2011; 39(2): 453-63.

[151] Pliszka M, Szablewski L. Glucose Transporters as a Target for Anticancer Therapy. Cancers (Basel). 2021; 13(16): 4184.

[152] Yang J, Virostko J, Liu J, Jarrett AM, Hormuth DA, 2nd, Yankeelov TE. Comparing mechanism-based and machine learning models for predicting the effects of glucose accessibility on tumor cell proliferation. Sci Rep. 2023; 13(1): 10387.

[153] Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med. 2011; 3(94): 94ra70.

[154] Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycl. arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2012; 11(8): 1672-82.

[155] Ojelabi OA, Lloyd KP, Simon AH, De Zutter JK, Carruthers A. WZB117 (2-Fluoro-6-(m-hydroxybenzoyloxy) Phenyl m-Hydroxybenzoate) Inhibits GLUT1-mediated Sugar Transport by Binding Reversibly at the Exofacial Sugar Binding Site. J Biol Chem. 2016; 291(52): 26762-72.

[156] Yakisich JS, Azad N, Kaushik V, Iyer AKV. The Biguanides Metformin and Buformin in Combination with 2-Deoxy-glucose or WZB-117 Inhibit the Viability of Highly Resistant Human Lung Cancer Cells. Stem Cells Int. 2019; 2019: 6254269.

[157] Wu Q, Ba-Alawi W. Deblois G, Cruickshank J, Duan S, Lima-Fernandes E. et al. GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer. Nat Commun. 2020; 11(1): 4205.

[158] Ma Y, Wang W, Idowu MO, Oh U, Wang XY, Temkin SM, et al. Ovarian Cancer Relies on Glucose Transporter 1 to Fuel Glycolysis and Growth: Anti-Tumor Activity of BAY-876. Cancers (Basel). 2018; 11(1): 33.

[159] Guo Z, Cheng Z, Wang J, Liu W, Peng H, Wang Y, et al. Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays. Angew Chem Int Ed Engl. 2019; 58(48): 17158-62.

[160] Casiraghi A, Bensimon A, Superti-Furga G. Recent developments in ligands and chemical probes targeting solute carrier transporters. Curr Opin Chem Biol. 2021; 62: 53-63.

[161] Zhang D, Wang Y, Dong L, Huang Y, Yuan J, Ben W, et al. Therapeutic role of EF24 targeting glucose transporter 1-mediated metabolism and metastasis in ovarian cancer cells. Cancer Sci. 2013; 104(12): 1690-6.

[162] Tilekar K, Upadhyay N, Iancu CV, Pokrovsky V, Choe JY, Ramaa CS. Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer. Biochim Biophys Acta Rev Cancer. 2020; 1874(2): 188457.

[163] Kapoor K, Finer-Moore JS. Pedersen BP, Caboni L, Waight A, Hillig RC, et al. Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides. Proc Natl Acad Sci U S A. 2016; 113(17): 4711-6.

[164] Allavena G, Del Bello B, Tini P, Volpi N, Valacchi G, Miracco C, et al. Trehalose inhibits cell proliferation and amplifies long-term temozolomide-and radiation-induced cytotoxicity in melanoma cells: A role for autophagy and premature senescence. J Cell Physiol. 2019; 234(7): 11708-21.

[165] Hevia D, Gonzalez-Menendez P. Quiros-Gonzalez I, Miar A, Rodriguez-Garcia A. Tan DX, et al. Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer. J Pineal Res. 2015; 58(2): 234-50.

[166] Hyun DH. Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts. Cancers (Basel). 2020; 12(7): 1822.

[167] Zambrano A, Molt M, Uribe E, Salas M. Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy. Int J Mol Sci. 2019; 20(13): 3374.

[168] Sage JM, Cura AJ, Lloyd KP, Carruthers A. Caffeine inhibits glucose transport by binding at the GLUT1 nucleotide-binding site. Am J Physiol Cell Physiol. 2015; 308(10): C827-34.

[169] Shahruzaman SH, Mustafa MF, Ramli S, Maniam S, Fakurazi S, Maniam S. The Cytotoxic Properties of Baeckea frutescens Branches Extracts in Eliminating Breast Cancer Cells. Evid Based Complement Alternat Med. 2019; 2019: 9607590.

[170] Ma X, Chen J, Huang B, Fu S, Qu S, Yu R, et al. ErbB2-upregulated HK1 and HK2 promote breast cancer cell proliferation, migration and invasion. Med Oncol. 2023; 40(5): 154.

[171] Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med. 2011; 208(2): 313-26.

[172] Wang L, Yang Q, Peng S, Liu X. The combination of the glycolysis inhibitor 2-DG and sorafenib can be effective against sorafenib-tolerant persister cancer cells. Onco Targets Ther. 2019; 12: 5359-73.

[173] Wang Z, Kang F, Gao Y, Liu Y, Xu X, Ma X, et al. Metformin Promotes 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase. Mol Imaging Biol. 2018; 20(3): 388-97.

[174] Tomizawa M, Shinozaki F, Motoyoshi Y, Sugiyama T, Yamamoto S, Ishige N. 2-Deoxyglucose and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells. Oncol Lett. 2017; 13(2): 800-4.

[175] Takemura A, Che XF, Tabuchi T, Moriya S, Miyazawa K, Tomoda A. Enhancement of cytotoxic and pro-apoptotic effects of 2-aminophenoxazine-3-one on the rat hepatocellular carcinoma cell line dRLh-84, the human hepatocellular carcinoma cell line HepG2, and the rat normal hepatocellular cell line RLN-10 in combination with 2-deoxy-D-glucose. Oncol Rep. 2012; 27(2): 347-55.

[176] Geschwind JF, Georgiades CS, Ko YH, Pedersen PL. Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther. 2004; 4(3): 449-57.

[177] Rai Y, Yadav P, Kumari N, Kalra N, Bhatt AN. Hexokinase II inhibition by 3-bromopyruvate sensitizes myeloid leukemic cells K-562 to anti-leukemic drug, daunorubicin. Biosci Rep. 2019; 39(9): BSR20190880.

[178] Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, et al. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. J Clin Oncol. 2002; 20(20): 4150-9.

[179] De Lena M, Lorusso V, Bottalico C, Brandi M, De Mitrio A, Catino A, et al. Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum. J Clin Oncol. 1997; 15(10): 3208-13.

[180] Nath K, Nelson DS, Heitjan DF, Leeper DB, Zhou R, Glickson JD. Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed. 2015; 28(3): 281-90.

[181] Dogliotti L, Berruti A, Buniva T, Zola P, Bau MG, Farris A, et al. Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J Clin Oncol. 1996; 14(4): 1165-72.

[182] Salani B, Marini C, Rio AD, Ravera S, Massollo M, Orengo AM, et al. Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci Rep. 2013; 3: 2070.

[183] Guo Y, Wei L, Zhou Y, Lu N, Tang X, Li Z, et al. Flavonoid GL-V9 induces apoptosis and inhibits glycolysis of breast cancer via disrupting GSK-3beta-modulated mitochondrial binding of HKII. Free Radic Biol Med. 2020; 146: 119-29.

[184] Zhang Q, Liu Q, Zheng S, Liu T, Yang L, Han X, et al. Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation. J Cancer. 2021; 12(16): 4830-40.

[185] Li W, Hao J, Zhang L, Cheng Z, Deng X, Shu G. Astragalin Reduces Hexokinase 2 through Increasing miR-125b to Inhibit the Proliferation of Hepatocellular Carcinoma Cells in Vitro and in Vivo. J Agric Food Chem. 2017; 65(29): 5961-72.

[186] Zhang HN, Yang L, Ling JY, Czajkowsky DM, Wang JF, Zhang XW, et al. Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic. Proc Natl Acad Sci U S A. 2015; 112(49): 15084-9.

[187] Liu Y, Yue J, Ren Z, He M, Wang A, Xie J, et al. Vitamin C enhances the sensitivity of osteosarcoma to arsenic trioxide via inhibiting aerobic glycolysis. Toxicol Appl Pharmacol. 2024; 482: 116798.

[188] Ling S, Shan Q, Liu P, Feng T, Zhang X, Xiang P, et al. Metformin ameliorates arsenic trioxide hepatotoxicity via inhibiting mitochondrial complex I. Cell Death Dis. 2017; 8(11): e3159.

[189] Dai W, Wang F, Lu J, Xia Y, He L, Chen K, et al. By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice. Oncotarget. 2015; 6(15): 13703-17.

[190] Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene. 2011; 30(42): 4297-306.

[191] Tao T, Su Q, Xu S, Deng J, Zhou S, Zhuang Y, et al. Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis. J Cell Physiol. 2019; 234(3): 3088-104.

[192] Shang D, Wu J, Guo L, Xu Y, Liu L, Lu J. Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2. Int J Oncol. 2017; 50(5): 1848-56.

[193] Liu M, Zhang Z, Wang H, Chen X, Jin C. Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2. Int J Biol Sci. 2019; 15(3): 617-27.

[194] Ivanova D, Zhelev Z, Getsov P, Nikolova B, Aoki I, Higashi T, et al. Vitamin K: Redox-modulation, prevention of mitochondrial dysfunction and anticancer effect. Redox Biol. 2018; 16: 352-8.

[195] Chen J, Jiang Z, Wang B, Wang Y, Hu X. Vitamin K(3) and K(5) are inhibitors of tumor pyruvate kinase M2. Cancer Lett. 2012; 316(2): 204-10.

[196] Ning X, Qi H, Li R, Li Y, Jin Y, McNutt MA, et al. Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase. Eur J Med Chem. 2017; 138: 343-52.

[197] Yang P, Ding GB, Liu W, Fu R, Sajid A, Li Z. Tannic acid directly targets pyruvate kinase isoenzyme M2 to attenuate colon cancer cell proliferation. Food Funct. 2018; 9(11): 5547-59.

[198] Son JY, Yoon S, Tae IH, Park YJ, De U, Jeon Y, et al. Novel therapeutic roles of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways. Cancer Med. 2018; 7(10): 5083-95.

[199] Feng J, Wu L, Ji J, Chen K, Yu Q, Zhang J, et al. PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma. J Exp Clin Cancer Res. 2019; 38(1): 204.

[200] Jin X, Min Q, Wang D, Wang Y, Li G, Wang Z, et al. FV-429 induces apoptosis by regulating nuclear translocation of PKM2 in pancreatic cancer cells. Heliyon. 2024; 10(8): e29515.

[201] Yu H, Yin Y, Yi Y, Cheng Z, Kuang W, Li R, et al. Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia. Cancer Commun (Lond). 2020; 40(10): 501-17.

[202] Koukourakis M, Tsolou A, Pouliliou S, Lamprou I, Papadopoulou M, Ilemosoglou M, et al. Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide. Biochem Biophys Res Commun. 2017; 491(4): 932-8.

[203] Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010; 107(5): 2037-42.

[204] Farabegoli F, Vettraino M, Manerba M, Fiume L, Roberti M, Di Stefano G. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur J Pharm Sci. 2012; 47(4): 729-38.

[205] Van Poznak C, Seidman AD, Reidenberg MM, Moasser MM, Sklarin N, Van Zee K, et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat. 2001; 66(3): 239-48.

[206] Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA, et al. Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab. 1993; 76(4): 1019-24.

[207] Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med. 2018; 7(12): 6124-36.

[208] Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther. 2008; 7(1): 110-20.

[209] Clem BF, O’Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y. Kerr DA, 2nd, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. 2013; 12(8): 1461-70.

[210] Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, et al. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer. 2019; 144(1): 178-89.

[211] Zhu Y, Lu L, Qiao C, Shan Y, Li H, Qian S, et al. Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor. Oncogene. 2018; 37(21): 2837-49.

[212] Wang Y, Qu C, Liu T, Wang C. PFKFB3 inhibitors as potential anticancer agents: Mechanisms of action, current developments, and structure-activit. relationships. Eur J Med Chem. 2020; 203: 112612.

[213] Bartrons R, Rodriguez-Garcia A. Simon-Molas H, Castano E, Manzano A, Navarro-Sabate A. The potential utility of PFKFB3 as a therapeutic target. Expert Opin Ther Targets. 2018; 22(8): 659-74.

[214] Grandjean G, de Jong PR, James B, Koh MY, Lemos R, Kingston J, et al. Definition of a Novel Feed-Forward Mechanism for Glycolysis-HIF1alpha Signaling in Hypoxic Tumors Highlights Aldolase A as a Therapeutic Target. Cancer Res. 2016; 76(14): 4259-69.

[215] Chang YC, Chiou J, Yang YF, Su CY, Lin YF, Yang CN, et al. Therapeutic Targeting of Aldolase A Interactions Inhibits Lung Cancer Metastasis and Prolongs Survival. Cancer Res. 2019; 79(18): 4754-66.

[216] Hu H, Zhu W, Qin J, Chen M, Gong L, Li L, et al. Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology. 2017; 65(2): 515-28.

[217] He Y, Luo Y, Zhang D, Wang X, Zhang P, Li H, et al. PGK1-mediated cancer progression and drug resistance. Am J Cancer Res. 2019; 9(11): 2280-302.

[218] Evans MJ, Saghatelian A, Sorensen EJ, Cravatt BF. Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nat Biotechnol. 2005; 23(10): 1303-7.

[219] Capello M, Ferri-Borgogno S. Riganti C, Chattaragada MS, Principe M, Roux C, et al. Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest. Oncotarget. 2016; 7(5): 5598-612.

[220] Muller FL, Colla S, Aquilanti E, Manzo VE, Genovese G, Lee J, et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature. 2012; 488(7411): 337-42.

[221] Lin J, Xia L, Liang J, Han Y, Wang H, Oyang L, et al. The roles of glucose metabolic reprogramming in chemo-and radio-resistance. J Exp Clin Cancer Res. 2019; 38(1): 218.

[222] Yang T, Ren C, Qiao P, Han X, Wang L, Lv S, et al. PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. Oncogene. 2018; 37(45): 5997-6009.

[223] Liu X, Miao W, Huang M, Li L, Dai X, Wang Y. Elevated Hexokinase II Expression Confers Acquired Resistance to 4-Hydroxytamoxifen in Breast Cancer Cells. Mol Cell Proteomics. 2019; 18(11): 2273-84.

[224] Sun ML, Wang GJ, Li J, Cui JW, Zhang AL, Wang ZN, et al. [Construction of shRNA eukaryotic expression vectors of pkm2 gene and their effect on drug resistant cell line of acute promyelocytic leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010; 18(1): 85-9.

[225] Nawaz MH, Ferreira JC, Nedyalkova L, Zhu H, Carrasco-Lopez C. Kirmizialtin S, et al. The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation. Biosci Rep. 2018; 38(1): BSR20171666.

[226] Shan W, Zhou Y, Tam KY. The development of small-molecule inhibitors targeting hexokinase 2. Drug Discov Today. 2022; 27(9): 2574-85.

[227] Xu S, Herschman HR. A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers. Cancer Res. 2019; 79(23): 5907-14.

[228] Huang Y, Ouyang F, Yang F, Zhang N, Zhao W, Xu H, et al. The expression of Hexokinase 2 and its hub genes are correlated with the prognosis in glioma. BMC Cancer. 2022; 22(1): 900.

[229] Yang H, Hou H, Zhao H, Yu T, Hu Y, Hu Y, et al. HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells. Front Oncol. 2021; 11: 794015.

[230] Wang J, Shao F, Yang Y, Wang W, Yang X, Li R, et al. A non-metabolic function of hexokinase 2 in small cell lung cancer: promotes cancer cell stemness by increasing USP11-mediated CD133 stability. Cancer Commun (Lond). 2022; 42(10): 1008-27.

[231] Hamabe A, Yamamoto H, Konno M, Uemura M, Nishimura J, Hata T, et al. Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase-E1alpha in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis. Cancer Sci. 2014; 105(9): 1100-8.

[232] Han J, Meng Q, Xi Q, Wang H, Wu G. PFKFB3 was overexpressed in gastric cancer patients and promoted the proliferation and migration of gastric cancer cells. Cancer Biomark. 2017; 18(3): 249-56.

[233] Chen L, Wu Z, Guo J, Wang X, Zhao Z, Liang H, et al. Initial clinical and experimental analyses of ALDOA in gastric cancer, as a novel prognostic biomarker and potential therapeutic target. Clin Exp Med. 2023; 23(6): 2443-56.

[234] Lu G, Shi W, Zhang Y. Prognostic Implications and Immune Infiltration Analysis of ALDOA in Lung Adenocarcinoma. Front Genet. 2021; 12: 721021.

[235] Jiang Z, Wang X, Li J, Yang H, Lin X. Aldolase A as a prognostic factor and mediator of progression via inducing epithelial-mesenchymal transition in gastric cancer. J Cell Mol Med. 2018; 22(9): 4377-86.

[236] Yang Y, Cui H, Li D, Gao Y, Chen L, Zhou C, et al. Prognosis and Immunological Characteristics of PGK1 in Lung Adenocarcinoma: A Systematic Analysis. Cancers (Basel). 2022; 14(21): 5228.

[237] Townsend MH, Ence ZE, Felsted AM, Parker AC, Piccolo SR, Robison RA, et al. Potential new biomarkers for endometrial cancer. Cancer Cell Int. 2019; 19: 19.

[238] Zieker D, Konigsrainer I, Tritschler I, Loffler M, Beckert S, Traub F, et al. Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer. Int J Cancer. 2010; 126(6): 1513-20.

[239] Sun Q, Li S, Wang Y, Peng H, Zhang X, Zheng Y, et al. Phosphoglyceric acid mutase-1 contributes to oncogenic mTOR-mediated tumor growth and confers non-small cell lung cancer patients with poor prognosis. Cell Death Differ. 2018; 25(6): 1160-73.

[240] Zhang D, Wu H, Zhang X, Ding X, Huang M, Geng M, et al. Phosphoglycerate Mutase 1 Predicts the Poor Prognosis of Oral Squamous Cell Carcinoma and is Associated with Cell Migration. J Cancer. 2017; 8(11): 1943-51.

[241] Huang Z, Yan Y, Wang T, Wang Z, Cai J, Cao X, et al. Identification of ENO1 as a prognostic biomarker and molecular target among ENOs in bladder cancer. J Transl Med. 2022; 20(1): 315.

[242] Hippner M, Majkowski M, Biecek P, Szkudlarek T, Simiczyjew A, Pieniazek M, et al. Alpha-Enolase (ENO1) Correlates with Invasiveness of Cutaneous Melanoma-An In Vitro and a Clinical Study. Diagnostics (Basel). 2022; 12(2): 254.

[243] Cancemi P, Buttacavoli M, Roz E, Feo S. Expression of Alpha-Enolase (ENO1), Myc Promoter-Bindin. Protein-1 (MBP-1) and Matrix Metalloproteinases (MMP-2 and MMP-9) Reflect the Nature and Aggressiveness of Breast Tumors. Int J Mol Sci. 2019; 20(16): 3952.

[244] White-Al Habeeb NM, Di Meo A, Scorilas A, Rotondo F, Masui O, Seivwright A, et al. Alpha-enolase is a potential prognostic marker in clear cell renal cell carcinoma. Clin Exp Metastasis. 2015; 32(6): 531-41.

[245] Chang H, Xu Q, Li J, Li M, Zhang Z, Ma H, et al. Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-kappaB pathway in HNSCC. Cell Death Dis. 2021; 12(8): 725.

[246] Mohammad GH, Olde Damink SW, Malago M, Dhar DK, Pereira SP. Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome. PLoS One. 2016; 11(3): e0151635.

[247] Girgis H, Masui O, White NM, Scorilas A, Rotondo F, Seivwright A, et al. Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma. Mol Cancer. 2014; 13: 101.

[248] Huang X, Li X, Xie X, Ye F, Chen B, Song C, et al. High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer. Breast. 2016; 30: 39-46.

[249] Li L, Fath MA, Scarbrough PM, Watson WH, Spitz DR. Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer. Redox Biol. 2015; 4: 127-35.

[250] Simons AL, Ahmad IM, Mattson DM, Dornfeld KJ, Spitz DR. 2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res. 2007; 67(7): 3364-70.

[251] Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, et al. 2-deoxy-D-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res. 2004; 64(1): 31-4.

[252] Zhang B, Chan SH, Liu XQ, Shi YY, Dong ZX, Shao XR, et al. Targeting hexokinase 2 increases the sensitivity of oxaliplatin by Twist1 in colorectal cancer. J Cell Mol Med. 2021; 25(18): 8836-49.

[253] Gadducci A, Brunetti I, Muttini MP, Fanucchi A, Dargenio F, Giannessi PG, et al. Epidoxorubicin and lonidamine in refractory or recurrent epithelial ovarian cancer. Eur J Cancer. 1994;30A(10): 1432-5.

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