Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase
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摘要
Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.Methods: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase(PDHA1) was tested in HEK293 T cells and clear cell renal cell carcinoma(cc RCC) specimens using gene knockdown, western blotting,immunohistochemistry, and immunofluorescence.Results: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase(PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in cc RCC.Conclusions: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.
Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.Methods: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase(PDHA1) was tested in HEK293 T cells and clear cell renal cell carcinoma(cc RCC) specimens using gene knockdown, western blotting,immunohistochemistry, and immunofluorescence.Results: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase(PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in cc RCC.Conclusions: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.
Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.Methods: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase(PDHA1) was tested in HEK293 T cells and clear cell renal cell carcinoma(cc RCC) specimens using gene knockdown, western blotting,immunohistochemistry, and immunofluorescence.Results: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase(PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in cc RCC.Conclusions: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.
引文
1.Liberti MV, Locasale JW. The Warburg Effect:How does it benefit cancer cells?. Trends Biochem Sci2016;41:211-8.
2 .Vander Heiden MG, Cantley LC, Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation. Science 2009;324:1029-33.
3 .Yao J, Liu J, Zhao W. By blocking hexokinase-2phosphorylation, limonin suppresses tumor glycolysis and induces cell apoptosis in hepatocellular carcinoma. Onco Targets Ther 2018;11:3793-803.
4 .Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection:Akting on mitochondria and TORCing to autophagy. Cell Death Differ 2015;22:248-57.
5 .Chen Z, Zhang H, Lu W, et al. Role of mitochondriaassociated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 2009;1787:553-60.
6 .Guo C, Ludvik AE, Arlotto ME, et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun 2015;6:6069.
7 .Irwin DM, Tan H. Molecular evolution of the vertebrate hexokinase gene family:Identification of a conserved fifth vertebrate hexokinase gene. Comp Biochem Physiol Part D Genomics Proteomics 2008;3:96-107.
8 .Patra KC, Wang Q, Bhaskar PT, et al. Hexokinase 2is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013;24:213-28.
9 .Ho N, Coomber BL. Hexokinase II expression is correlated with colorectal cancer prognosis. Cancer Treat Commun 2016;6:11-6.
10 .Ho N, Morrison J, Silva A, et al. The effect of 3-bromopyruvate on human colorectal cancer cells is dependent on glucose concentration but not hexokinase II expression. Biosci Rep 2016;36:e00299.
11 .Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2bound to mitochondria:cancer’s stygian link to the“Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 2009;19:17-24.
12 .Wolf AJ, Reyes CN, Liang W, et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 2016;166:624-36.
13 .Roberts DJ, Tan-Sah VP, Smith JM, et al. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem 2013;288:23798-806.
14 .Majewski N, Nogueira V, Bhaskar P, et al.Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 2004;16:819-30.
15 .Gall JM, Wong V, Pimental DR, et al. Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress. Kidney Int 2011;79:1207-16.
16 .Singh A, Sen E. Reciprocal role of SIRT6 and Hexokinase 2 in the regulation of autophagy driven monocyte differentiation. Exp Cell Res 2017;360:365-74.
17 .Roberts DJ, Tan-Sah VP, Ding EY, et al.Hexokinase-II positively regulates glucose starvationinduced autophagy through TORC1 inhibition. Mol Cell 2014;53:521-33.
18 .Adams V, Griffin LD, Gelb BD, et al. Protein kinase activity of rat brain hexokinase. Biochem Biophys Res Commun 1991;177:1101-6.
19 .Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes.FASEB J 1990;4:3224-33.
20 .Patel MS, Korotchkina LG. Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans2006;34:217-22.
21 .Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007;64:830-49.
22 .Hiromasa Y, Fujisawa T, Aso Y, et al. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3components. J Biol Chem 2004;279:6921-33.
23 .Lu CW, Lin SC, Chen KF, et al. Induction of pyruvate dehydrogenase kinase-3 by hypoxiainducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 2008;283:28106-14.
24 .Wynn RM, Kato M, Chuang JL, et al. Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. J Biol Chem 2008;283:25305-15.
25 .Mc Fate T, Mohyeldin A, Lu H, et al. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem2008;283:22700-8.
26 .Ferriero R, Iannuzzi C, Manco G, et al. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis 2015;38:895-904.
27 .Kato M, Li J, Chuang JL, et al. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure 2007;15:992-1004.
28 .Hitosugi T, Fan J, Chung TW, et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 2011;44:864-77.
29 .Shan C, Kang HB, Elf S, et al. Tyr-94phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem 2014;289:21413-22.
30 .Fan J, Shan C, Kang HB, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53:534-48.
31 .Park J, Chen Y, Tishkoff DX, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 2013;50:919-30.
32 .Turajlic S, Larkin J, Swanton C. Snap Shot:renal cell carcinoma. Cell 2015;163:1556-1556.
33 .Ricketts CJ, Crooks DR, Sourbier C, et al. Snap Shot:renal cell carcinoma. Cancer Cell 2016;29:610-610.
34 .Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008;8:705-13.
35 .Knight JD, Tian R, Lee RE, et al. A novel whole-cell lysate kinase assay identifies substrates of the p38MAPK in differentiating myoblasts. Skelet Muscle2012;2:5.
36 .Wang C, Ye M, Bian Y, et al. Determination of CK2specificity and substrates by proteome-derived peptide libraries. J Proteome Res 2013;12:3813-21.
37 .Tsai HJ, Wilson JE. Functional organization of mammalian hexokinases:both N-and C-terminal halves of the rat type II isozyme possess catalytic sites.Arch Biochem Biophys 1996;329:17-23.
38 .Wilson JE. Isozymes of mammalian hexokinase:structure, subcellular localization and metabolic function. J Exp Biol 2003;206:2049-57.
39 .Mathupala SP, Ko YH, Pedersen PL. Hexokinase II:cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 2006;25:4777-86.
40 .Hu JW, Sun P, Zhang DX, et al. Hexokinase 2regulates G1/S checkpoint through CDK2 in cancerassociated fibroblasts. Cell Signal 2014;26:2210-6.
41 .Ko YH, Verhoeven HA, Lee MJ, et al. A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate(3BP)as a potent anticancer agent:from bench side to bedside. J Bioenerg Biomembr 2012;44:163-70.
42 .Ko YH, Pedersen PL, Geschwind JF. Glucose catabolism in the rabbit VX2 tumor model for liver cancer:characterization and targeting hexokinase.Cancer Lett 2001;173:83-91.
43 .Sutendra G, Kinnaird A, Dromparis P, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-Co A and histone acetylation. Cell 2014;158:84-97.
44 .Ozden O, Park SH, Wagner BA, et al. SIRT3deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med 2014;76:163-72.
45 .Mathias RA, Greco TM, Oberstein A, et al. Sirtuin 4is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159:1615-25.
46 .Kaplon J, Zheng L, Meissl K, et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013;498:109-12.
47 .Hosios AM, Fiske BP, Gui DY, et al. Lack of evidence for PKM2 protein kinase activity. Mol Cell 2015;59:850-7.
48 .Yang W, Xia Y, Ji H, et al. Nuclear PKM2 regulatesβ-catenin transactivation upon EGFR activation.Nature 2011;480:118-22.
49 .Gao X, Wang H, Yang JJ, et al. Pyruvate kinase M2regulates gene transcription by acting as a protein kinase. Mol Cell 2012;45:598-609.
50 .Yang W, Xia Y, Hawke D, et al. PKM2phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2014;158:1210.
51 .Jiang Y, Li X, Yang W, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell 2014;53:75-87.
52 .Jiang Y, Wang Y, Wang T, et al. PKM2phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat Commun 2014;5:5566.
53 .Keller KE, Doctor ZM, Dwyer ZW, et al. SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol Cell 2014;53:700-9.
54 .He CL, Bian YY, Xue Y, et al. Pyruvate kinase M2activates m TORC1 by phosphorylating AKT1S1. Sci Rep 2016;6:21524.
55 .Li X, Jiang Y, Meisenhelder J, et al. Mitochondriatranslocated PGK1 functions as a protein kinase to coordinate glycolysis and the TCA cycle in tumorigenesis. Mol Cell 2016;61:705-19.
56 .Qian X, Li X, Cai Q, et al. Phosphoglycerate kinase 1phosphorylates beclin1 to induce autophagy. Mol Cell2017;65:917-31.
57 .Li TY, Sun Y, Liang Y, et al. ULK1/2 constitute a bifurcate node controlling glucose metabolic fluxes in addition to autophagy. Mol Cell 2016;62:359-70.
58 .Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells:identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 2001;276:43407-12.
59 .Gwak GY, Yoon JH, Kim KM, et al. Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression. J Hepatol 2005;42:358-64.
2 .Vander Heiden MG, Cantley LC, Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation. Science 2009;324:1029-33.
3 .Yao J, Liu J, Zhao W. By blocking hexokinase-2phosphorylation, limonin suppresses tumor glycolysis and induces cell apoptosis in hepatocellular carcinoma. Onco Targets Ther 2018;11:3793-803.
4 .Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection:Akting on mitochondria and TORCing to autophagy. Cell Death Differ 2015;22:248-57.
5 .Chen Z, Zhang H, Lu W, et al. Role of mitochondriaassociated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 2009;1787:553-60.
6 .Guo C, Ludvik AE, Arlotto ME, et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun 2015;6:6069.
7 .Irwin DM, Tan H. Molecular evolution of the vertebrate hexokinase gene family:Identification of a conserved fifth vertebrate hexokinase gene. Comp Biochem Physiol Part D Genomics Proteomics 2008;3:96-107.
8 .Patra KC, Wang Q, Bhaskar PT, et al. Hexokinase 2is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013;24:213-28.
9 .Ho N, Coomber BL. Hexokinase II expression is correlated with colorectal cancer prognosis. Cancer Treat Commun 2016;6:11-6.
10 .Ho N, Morrison J, Silva A, et al. The effect of 3-bromopyruvate on human colorectal cancer cells is dependent on glucose concentration but not hexokinase II expression. Biosci Rep 2016;36:e00299.
11 .Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2bound to mitochondria:cancer’s stygian link to the“Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 2009;19:17-24.
12 .Wolf AJ, Reyes CN, Liang W, et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 2016;166:624-36.
13 .Roberts DJ, Tan-Sah VP, Smith JM, et al. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem 2013;288:23798-806.
14 .Majewski N, Nogueira V, Bhaskar P, et al.Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 2004;16:819-30.
15 .Gall JM, Wong V, Pimental DR, et al. Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress. Kidney Int 2011;79:1207-16.
16 .Singh A, Sen E. Reciprocal role of SIRT6 and Hexokinase 2 in the regulation of autophagy driven monocyte differentiation. Exp Cell Res 2017;360:365-74.
17 .Roberts DJ, Tan-Sah VP, Ding EY, et al.Hexokinase-II positively regulates glucose starvationinduced autophagy through TORC1 inhibition. Mol Cell 2014;53:521-33.
18 .Adams V, Griffin LD, Gelb BD, et al. Protein kinase activity of rat brain hexokinase. Biochem Biophys Res Commun 1991;177:1101-6.
19 .Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes.FASEB J 1990;4:3224-33.
20 .Patel MS, Korotchkina LG. Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans2006;34:217-22.
21 .Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007;64:830-49.
22 .Hiromasa Y, Fujisawa T, Aso Y, et al. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3components. J Biol Chem 2004;279:6921-33.
23 .Lu CW, Lin SC, Chen KF, et al. Induction of pyruvate dehydrogenase kinase-3 by hypoxiainducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 2008;283:28106-14.
24 .Wynn RM, Kato M, Chuang JL, et al. Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. J Biol Chem 2008;283:25305-15.
25 .Mc Fate T, Mohyeldin A, Lu H, et al. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem2008;283:22700-8.
26 .Ferriero R, Iannuzzi C, Manco G, et al. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis 2015;38:895-904.
27 .Kato M, Li J, Chuang JL, et al. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure 2007;15:992-1004.
28 .Hitosugi T, Fan J, Chung TW, et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 2011;44:864-77.
29 .Shan C, Kang HB, Elf S, et al. Tyr-94phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem 2014;289:21413-22.
30 .Fan J, Shan C, Kang HB, et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53:534-48.
31 .Park J, Chen Y, Tishkoff DX, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 2013;50:919-30.
32 .Turajlic S, Larkin J, Swanton C. Snap Shot:renal cell carcinoma. Cell 2015;163:1556-1556.
33 .Ricketts CJ, Crooks DR, Sourbier C, et al. Snap Shot:renal cell carcinoma. Cancer Cell 2016;29:610-610.
34 .Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008;8:705-13.
35 .Knight JD, Tian R, Lee RE, et al. A novel whole-cell lysate kinase assay identifies substrates of the p38MAPK in differentiating myoblasts. Skelet Muscle2012;2:5.
36 .Wang C, Ye M, Bian Y, et al. Determination of CK2specificity and substrates by proteome-derived peptide libraries. J Proteome Res 2013;12:3813-21.
37 .Tsai HJ, Wilson JE. Functional organization of mammalian hexokinases:both N-and C-terminal halves of the rat type II isozyme possess catalytic sites.Arch Biochem Biophys 1996;329:17-23.
38 .Wilson JE. Isozymes of mammalian hexokinase:structure, subcellular localization and metabolic function. J Exp Biol 2003;206:2049-57.
39 .Mathupala SP, Ko YH, Pedersen PL. Hexokinase II:cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 2006;25:4777-86.
40 .Hu JW, Sun P, Zhang DX, et al. Hexokinase 2regulates G1/S checkpoint through CDK2 in cancerassociated fibroblasts. Cell Signal 2014;26:2210-6.
41 .Ko YH, Verhoeven HA, Lee MJ, et al. A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate(3BP)as a potent anticancer agent:from bench side to bedside. J Bioenerg Biomembr 2012;44:163-70.
42 .Ko YH, Pedersen PL, Geschwind JF. Glucose catabolism in the rabbit VX2 tumor model for liver cancer:characterization and targeting hexokinase.Cancer Lett 2001;173:83-91.
43 .Sutendra G, Kinnaird A, Dromparis P, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-Co A and histone acetylation. Cell 2014;158:84-97.
44 .Ozden O, Park SH, Wagner BA, et al. SIRT3deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med 2014;76:163-72.
45 .Mathias RA, Greco TM, Oberstein A, et al. Sirtuin 4is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 2014;159:1615-25.
46 .Kaplon J, Zheng L, Meissl K, et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013;498:109-12.
47 .Hosios AM, Fiske BP, Gui DY, et al. Lack of evidence for PKM2 protein kinase activity. Mol Cell 2015;59:850-7.
48 .Yang W, Xia Y, Ji H, et al. Nuclear PKM2 regulatesβ-catenin transactivation upon EGFR activation.Nature 2011;480:118-22.
49 .Gao X, Wang H, Yang JJ, et al. Pyruvate kinase M2regulates gene transcription by acting as a protein kinase. Mol Cell 2012;45:598-609.
50 .Yang W, Xia Y, Hawke D, et al. PKM2phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 2014;158:1210.
51 .Jiang Y, Li X, Yang W, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell 2014;53:75-87.
52 .Jiang Y, Wang Y, Wang T, et al. PKM2phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat Commun 2014;5:5566.
53 .Keller KE, Doctor ZM, Dwyer ZW, et al. SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol Cell 2014;53:700-9.
54 .He CL, Bian YY, Xue Y, et al. Pyruvate kinase M2activates m TORC1 by phosphorylating AKT1S1. Sci Rep 2016;6:21524.
55 .Li X, Jiang Y, Meisenhelder J, et al. Mitochondriatranslocated PGK1 functions as a protein kinase to coordinate glycolysis and the TCA cycle in tumorigenesis. Mol Cell 2016;61:705-19.
56 .Qian X, Li X, Cai Q, et al. Phosphoglycerate kinase 1phosphorylates beclin1 to induce autophagy. Mol Cell2017;65:917-31.
57 .Li TY, Sun Y, Liang Y, et al. ULK1/2 constitute a bifurcate node controlling glucose metabolic fluxes in addition to autophagy. Mol Cell 2016;62:359-70.
58 .Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells:identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 2001;276:43407-12.
59 .Gwak GY, Yoon JH, Kim KM, et al. Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression. J Hepatol 2005;42:358-64.