Activation of the Warburg Effect by Pyruvate Kinase M2 Promotes the Occurrence and Development of Liver Cancer

VIEWS - 274 (Abstract) 50 (PDF)
Mingyue Zhu, Mengsen Li, Yuli Zhou

Abstract


Abstract: Liver cancer, which is one of the most common malignancies, has a high incidence and case fatality rate, and is the third most common cause of death attributed to cancer. Warburg effect is a form of modified cell metabolism by which tumor cells obtain energy by glycolysis instead of oxidative phosphorylation, whether in an aerobic or anaerobic environment. It plays an important role in tumor proliferation, growth, invasion, and treatment. Pyruvate kinase M2 (PKM2), an essential key enzyme in the glycolytic process, is significantly elevated in multiple tumor tissues and plays a crucial role in the Warburg effect. Recently, increasing attention has been devoted to the mechanism of action of PKM2 in tumors, and interference with the glycolysis pathway is one of the new strategies for cancer treatment. This paper provides a review of the Warburg effect of PKM2 activation and its relationship with tumorigenesis and development and the potential value of Warburg effect in clinical diagnosis, treatment, and prognostic evaluation of liver cancer.


Keywords


Pyruvate kinase M2, Warburg effect, Hepatocellular carcinoma

Full Text:

Download PDF

References


Forner A, Reig M, Bruix J, 2019, Hepatocellular Carcinoma. Lancet, 391(10127):1301–4. DOI: 10.1016/ S0140-6736(18)30010-2

Tseng CH, Hsu YC, Chen TH, et al., 2021, Hepatocellular Carcinoma Incidence with Tenofovir Versus Entecavir in Chronic Hepatitis B: A Systematic Review and Meta-Analysis. Lancet Gastroenterol Hepatol, 5(12):1039–52. DOI: 10.1016/S2468-1253(20)30249-1.

Liu Z, Jiang Y, Yuan H, et al., 2019, The Trends in Incidence of Primary Liver Cancer Caused by Specific Etiologies: Results from the Global Burden of Disease Study 2016 and Implications for Liver Cancer Prevention. J Hepatol, 70(4):674–83. DOI: 10.1016/j.jhep.2018.12.001.

Lee M, Ko H, Yun M, 2018, Cancer Metabolism as a Mechanism of Treatment Resistance and Potential Therapeutic Target in Hepatocellular Carcinoma. Yonsei Med J, 59:1143–9. DOI: 10.3349/ymj.2018.59.10.1143.

Warburg O, 1956, On the Origin of Cancer Cells. Science, 123(3191):309–14. DOI: 10.1126/science.123.3191.309.

Vander Heiden MG, Cantley LC, Thompson CB, 2009, Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science, 324(5930):1029–33. DOI: 10.1126/science.1160809.

Mazurek S, 2011, Pyruvate Kinase Type M2: A Key Regulator of the Metabolic Budget System in Tumor Cells. Int J Biochem Cell Biol, 43(7):969–80. DOI: 10.1016/j. biocel.2010.02.005.

Otto AM, 2016, Warburg Effect(s)-a Biographical Sketch of Otto Warburg and his Impacts on Tumor Metabolism. Cancer Metab, 4:5. DOI: 10.1186/s40170-016-0145-9.

Gupta V, Bamezai RN, 2010, Human Pyruvate Kinase M2: A Multifunctional Protein. Protein Sci, 19(11):2031–44. DOI: 10.1002/pro.505.

Israelsen WJ, Dayton TL, Davidson SM, et al., 2013, PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells. Cell, 155(2):397–409. DOI: 10.1016/j.cell.2013.09.025.

Wong CC, Au SL, Tse AP, et al., 2014, Switching of Pyruvate Kinase Isoform L to M2 Promotes Metabolic Reprogramming in Hepatocarcinogenesis. PLoS One, 9(12):e115036. DOI: 10.1371/journal.pone. 0115036.

Lv L, Xu YP, Zhao D, et al., 2013, Mitogenic and Oncogenic Stimulation of K433 Acetylation Promotes PKM2 Protein Kinase Activity and Nuclear Localization. Mol Cell, 52(3):340–52. DOI: 10.1016/j.molcel.2013.09.004.

Mazurek S, 2007, Pyruvate Kinase Type M2: A Key Regulator Within the Tumour Metabolome and a Tool for Metabolic Profiling of Tumours. Ernst Schering Found Symp Proc, 4:99–124. DOI: 10.1007/2789_2008_091.

Miccheli A, Tomassini A, Puccetti C, et al., 2006, Metabolic Profiling by 13C-NMR Spectroscopy: [1, 2-13C2] Glucose Reveals a Heterogeneous Metabolism in Human Leukemia T Cells. Biochimie, 88(5):437–48. DOI: 10.1016/j. biochi.2005.10.004.

Dombrauckas JD, Santarsiero BD, Mesecar AD, et al., 2005, Structural Basis for Tumor Pyruvate Kinase M2 Allosteric Regulation and Catalysis. Biochemistry, 44(27):9417–29. DOI: 10.1021/bi0474923.

Hitosugi T, Kang S, Heiden MG, et al., 2009, Tyrosine phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth. Sci Signal, 2(97):ra73. DOI: 10.1126/scisignal.2000431.

Shang Y, He J, Wang Y, et al., 2017, CHIP/Stub1 Regulates the Warburg Effect by Promoting Degradation of PKM2 in Ovarian Carcinoma. Oncogene, 36(29):4191–200. DOI: 10.1038/onc.2017.31.

Desai S, Ding M, Wang B, et al., 2014, Tissue-Specific Isoform Switch and DNA Hypomethylation of the Pyruvate Kinase PKM Gene in Human Cancers. Oncotarget, 5(18):8202–10. DOI: 10.18632/oncotarget.1159.

Wang Z, Chatterjee D, Jeon HY, et al., 2012, Exon-Centric Regulation of Pyruvate Kinase M Alternative Splicing Via Mutually Exclusive Exons. J Mol Cell Biol, 4(2):79–87. DOI: 10.1093/jmcb/mjr030.

Chen M, David CJ, Manley JL, 2012, Concentration Dependent Control of Pyruvate Kinase M Mutually Exclusive Splicing by hnRNP Proteins. Nat Struct Biol, 19(3):346–54. DOI: 10.1038/nsmb.2219.

Taniguchi K, Ito Y, Sugito N, et al., 2015, Organ-Specific PTB1-Associated microRNAs Determine Expression of Pyruvate Kinase Isoforms. Sci Rep, 5:8647. DOI: 1038/ srep08647.

Gu Z, Xia J, Xu H, et al., 2017, NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase. J Hematol Oncol, 10(1):17. DOI: 10.1186/s13045-017-0392-4.

Su CH, Hung KY, Hung SC, et al., 2017, RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M. Cell Mol Biol, 37(3):e00466–516. DOI: 10.1128/ MCB.00466-16.

Christofk HR, Heiden MG, Harris MH, et al., 2008, The M2 Splice Isoform of Pyruvate Kinase is Important for Cancer Metabolism and Tumour Growth. Nature, 452(7184):230–3. DOI: 10.1038/nature06734.

Cairns RA, Harris IS, Mak TW, 2011, Regulation of cancer cell metabolism. Nat Rev Cancer, 11(2):85–95. DOI: 10.1038/nrc2981.

Ye J, Mancuso A, Tong X, et al., 2012, Pyruvate Kinase M2 Promotes De Novo Serine Synthesis to Sustain mTORC1 Activity and Cell Proliferation. Proc Natl Acad Sci USA, 109(18):6904–9. DOI: 10.1073/pnas.1204176109.

Nakatsu D, Horiuchi Y, Kano F, et al., 2015, L-Cysteine Reversibly Inhibits Glucose-Induced Biphasic Insulin Secretion and ATP Production by Inactivating PKM2. Proc Natl Acad Sci USA, 112(10):E1067–76. DOI: 10.1073/ pnas.1417197112.

Xu Q, Tu J, Dou C, et al., 2017, HSP90 Promotes Cell Glycolysis, Proliferation and Inhibits Apoptosis by Regulating PKM2 Abundance via Thr-328 Phosphorylation in Hepatocellular Carcinoma. Mol Cancer, 16(1):178. DOI: 10.1186/s12943-017-0748-y.

Christofk HR, Heiden MG, Wu N, et al., 2008, Pyruvate Kinase M2 is a Phosphotyrosine-Binding Protein. Nature, 452(7184):181–6. DOI: 10.1038/nature06667.

Li Z, Yang P, Li Z, 2014, The Multifaceted Regulation and Functions of PKM2 in Tumor Progression. Biochim Biophys Acta, 1846(2):285–96. DOI: 10.1016/j.bbcan.2014.07.008.

Kedar VP, Zucconi BE, Wilson GM, et al., 2012, Direct Binding of Specific AUF1 Isoforms to Tandem Zinc Finger Domains of Tristetraprolin (TTP) Family Proteins. J Biol Chem, 287(8):5459–71. DOI: 10.1074/jbc.M111.312652.

Li L, Zhang Y, Qiao J, et al., 2014, Pyruvate Kinase M2 in Blood Circulation Facilitates Tumor Growth by Promoting Angiogenesis. J Biol Chem, 289(37):25812–21. DOI: 10.1074/jbc.M114.576934.

Azoitei N, Becher A, Steinestel K, et al., 2016, PKM2 Promotes Tumor Angiogenesis by Regulating HIF 1α Through NF-κB Activation. Mol Cancer, 15:3. DOI: 10.1186/s12943-015-0490-2.

Xu Q, Liu LZ, Yin Y, et al., 2015, Regulatory Circuit of PKM2/NF- κB/miR- 148a/152-Modulated Tumor Angiogenesis and Cancer Progression. Oncogene, 34(43):5482–93. DOI: 10.1038/onc.2015.6.

Kalbasi A, Ribas A, 2020, Tumour-Intrinsic Resistance to Immune Checkpoint Blockade. Nat Rev Immunol, 20(1):25–39. DOI: 10.1038/s41577-019-0218-4.

Herbst RS, Baas P, Kim DW, et al., 2016, Pembrolizumab Versus Docetaxel for Previously Treated, PD-L1-Positive, Advanced Non-Small-Cell Lung Cancer (KEYNOTE-010): ARandomised Controlled Trial. Lancet, 387(10027):1540–50. DOI: 10.1016/S0140-6736(15)01281-7.

Gandini S, Massi D, Mandalà M, 2016, PD-L1 Expression in Cancer Patients Receiving Anti PD-1/PD L1 Antibodies: A Systematic Review and Meta-Analysis. Crit Rev Oncol Hematol, 100:88–98. DOI: 10.1016/j. critrevonc.2016.02.001.

Feng Z, Rong P, Wang W, 2020, Meta-Analysis of the Efficacy and Safety of PD-1/PD-L1 Inhibitors Administered Alone or in Combination with anti-VEGF Agents in Advanced Hepatocellular Carcinoma. Gut, 69(10):1904–6. DOI: 10.1136/gutjnl-2019-320116.

Havel JJ, Chowell D, Chan TA, 2019, The Evolving Landscape of Biomarkers for Checkpoint Inhibitor Immunotherapy. Nat Rev Cancer, 19(3):133–50. DOI: 10. 1038/s41568- 019- 0116- x.

Finn RS, Ryoo BY, Merle P, et al., 2020, Pembrolizumab as Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol, 38(3):193–202. DOI: 10.1200/JCO.19.01307.

Finn RS, Qin S, Ikeda M, et al., 2020, Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med, 382(20):1894–905. DOI: 10.1056/ NEJMoa1915745.

Li TE, Wang S, Shen XT, et al., 2020, PKM2 Drives Hepatocellular Carcinoma Progression by Inducing Immunosuppressive Microenvironment. Front Immunol, 11:589997. DOI: 10.3389/fimmu.2020.589997.

Choi SY, Collins CC, Gout PW, et al., 2013, Cancer-Generated Lactic Acid: A Regulatory, Immunosuppressive Metabolite? J Pathol, 230(4):350–5. DOI: 10.1002/path.4218.

Romero-Garcia S, Moreno-Altamirano MM, Prado Garcia H, et al., 2016, Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance. Front Immunol, 7:52. DOI: 10.3389/fimmu.2016.00052.

Brand A, Singer K, Koehl GE, et al., 2016, LDHA Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab, 24(5):657–71. DOI: 10.1016/j.cmet.2016.08.011.

Fischer K, Hoffmann P, Voelkl S, et al., 2007, Inhibitory Effect of Tumor Cell-Derived Lactic Acid on Human T Cells. Blood, 109(9):3812–9. DOI: 10.1182/ blood-2006-07-035972.

Cassim S, Pouyssegur J, 2019, Tumor Microenvironment: A Metabolic Player that Shapes the Immune Response. Int J Mol Sci, 21(1):157. DOI: 10.3390/ijms21010157.

Li W, Tanikawa T, Kryczek I, et al., 2018, Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple Negative Breast Cancer. Cell Metab, 28(1):87–103.e6. DOI: 10.1016/j.cmet.2018.04.022.

Goldberg MS, Sharp PA, 2012, Pyruvate Kinase M2- Specific siRNA Induces Apoptosis and Tumor Regression. J Exp Med, 209(2):217–24. DOI: 10.1084/jem.20111487.

Youle RJ, Strasser A, 2008, The BCL-2 Protein Family: Opposing Activities that Mediate Cell Death. Nat Rev Mol Cell Biol, 9(1):47–59. DOI: 10.1038/nrm2308.

Bouillet P, Huang DC, O’Reilly LA, et al., 2000, The Role of the Pro-Apoptotic Bcl-2 Family Member Bim in Physiological Cell Death. Ann N Y Acad Sci, 926:83–9. DOI: 10.1111/j.1749-6632.2000.tb05601.x.

Moujalled D, Weston R, Anderton H, et al., 2011, Cyclic-AMP-Dependent Protein Kinase a Regulates Apoptosis by Stabilizing the BH3-Only Protein Bim. EMBO Rep, 2(1):77–83. DOI: 10.1038/embor.2010.190.

Ambrosini G, Seelman SL, Schwartz GK, 2009, Differentiation-Related Gene-1 Decreases Bim Stabil Ity by Proteasome-Mediated Degradation. Cancer Res, 69(15):6115–21. DOI: 10.1158/0008-5472.

Akiyama T, Dass CR, Choong PF, 2009, Bim-Targeted Cancer Therapy: A Link Between Drug Action and Underlying Molecular Changes. Mol Cancer Ther, 8(12):3173–80. DOI: 10.1158/1535-7163.

Hu W, Lu SX, Li M, et al., 2015, Pyruvate Kinase M2 Prevents Apoptosis via Modulating Bim Stability and Associates with Poor Outcome in Hepatocellular Carcinoma. Oncotarget, 6(9):6570–83. DOI: 10.18632/ oncotarget.3262.

Steták A, Veress R, Ovádi J, et al., 2007, Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death. Cancer Res, 67(4):1602– 8. DOI: 10.1158/0008-5472.

Tang Q, Ji Q, Xia W, et al., 2015, Pyruvate Kinase M2 Regulates Apoptosis of Intestinal Epithelial Cells in Crohn’s Disease. Dig Dis Sci, 60(2):393–404. DOI: 10.1007/ s10620-014-3189-0.

Kwon OH, Kang TW, Kim JH, et al., 2012, Pyruvate Kinase M2 Promotes the Growth of Gastric Cancer Cells Via Regulation of Bcl-xL Expression at Transcriptional Level. Biochem Biophys Res Commun, 423(1):38–44. DOI: 10.1016/j.bbrc.2012.05.063.

Hamabe A, Konno M, Tanuma N, et al., 2014, Role of Pyruvate Kinase M2 in Transcriptional Regulation Leading to Epithelial-Mesenchymal Transition. Proc Natl Acad Sci USA, 111(43):15526–31. DOI: 10.1073/pnas.1407717111.

Wang C, Li Y, Yan S, et al., 2020, Interactome Analysis Reveals that lncRNA HULC Promotes Aerobic Glycolysis Through LDHA and PKM2. Nat Commun, 11(1):3162. DOI: 10.1038/s41467-020-16966-3.

Chen Z, Lu X, Wang Z, et al., 2015, Co-Expression of PKM2 and TRIM35 Predicts Survival and Recurrence in Hepatocellular Carcinoma. Oncotarget, 6(4):2538–48. DOI: 10.18632/oncotarget.2991.

Lo CH, Farina F, Morris HP, et al., 1968, Glycolytic Regulation in Rat Liver and Hepatomas. Adv Enzyme Regul, 6:453–64. DOI: 10.1016/0065-2571(68)90028-9.

Feng C, Gao Y, Wang C, et al., 2013, Aberrant Overexpression of Pyruvate Kinase M2 is Associated with Aggressive Tumor Features and the BRAF Mutation in Papillary Thyroid Cancer. J Clin Endocrinol Metab, 98(9):E1524–33. DOI: 10.1210/jc.2012-4258.

Gumińska M, Stachurska MB, Ignacak J, 1988, Pyruvate Kinase Isoenzymes in Chromatin Extracts of Ehrlich Ascites Tumour, Morris Hepatoma 7777 and Normal Mouse and rat Livers. Biochim Biophys Acta, 966(2):207–13. DOI: 10.1016/0304-4165(88)90113-4.

Jeffery J, Lewis SJ, Ayling RM, 2009, Fecal Dimeric M2-Pyruvate Kinase (Tumor M2-PK) in the Differential Diagnosis of Functional and Organic Bowel Disorders. Inflamm Bowel Dis, 5(11):1630–4. DOI: 10.1002/ibd.20946.

Wang C, Delogu S, Ho C, et al., 2012, Inactivation of Spry2 Accelerates AKT-Driven Hepatocarcinogenesis Via Activation of MAPK and PKM2 Pathways. J Hepatol, 57(3):577–83. DOI: 10.1016/j.jhep.2012.04.026.

Liu WR, Tian MX, Yang LX, et al., 2015, PKM2 Promotes Metastasis by Recruiting Myeloid-Derived Suppressor Cells and Indicates Poor Prognosis for Hepatocellular Carcinoma. Oncotarget, 6(2):846–61. DOI: 10.18632/ oncotarget.2749.

Hong W, Guan KL, 2012, The YAP and TAZ Transcription Co-Activators: Key Downstream Effectors of the Mammalian Hippo Pathway. Semin Cell Dev Biol, 23(7):785–93. DOI: 10.1016/j.semcdb.2012.05.004.

Johnson R, Halder G, 2014, The Two Faces of Hippo: Targeting the Hippo Pathway for Regenerative Medicine and Cancer Treatment. Nat Rev Drug Discov, 13(1):63–79. DOI: 10.1038/nrd4161.

Rong O, Fei Y, Jun M, et al., 2019, Inhibition of Hippo Signaling by PKM2 Promotes Proliferation and Invasion and Migration of HCC Cells. J Nanjing Med Univ, 39(8):1183–7.

Mendonsa AM, Na TY, Gumbiner BM, 2018, E-Cadherin in Contact Inhibition and Cancer. Oncogene, 37(35):4769–80. DOI: 10.1038/s41388-018-0304-2.

Bure IV, Nemtsova MV, Zaletaev DV, 2019, Roles of E-Cadherin and Noncoding RNAs in the Epithelial-Mesenchymal Transition and Progression in Gastric Cancer. Int J Mol Sci, 20(12):2870. DOI: 10.3390/ijms20122870.

Chen YL, Song JJ, Chen XC, et al., 2015, Mechanisms of Pyruvate Kinase M2 Isoform Inhibits Cell Motility in Hepatocellular Carcinoma Cells. World J Gastroenterol, 21(30):9093–102. DOI: 10.3748/wjg.v21.i30.9093.

Arora PD, McCulloch CA, 1996, Dependence of Fibroblast Migration on Actin Severing Activity of Gelsolin. J Biol Chem, 271(34):20516–23. DOI: 10.1074/jbc.271.34.20516.

Piccolo E, Innominato PF, Mariggio MA, et al., 2002, The Mechanism Involved in the Regulation of Phospholipase Cgamma1 Activity in Cell Migration. Oncogene, 21(42):6520–9. DOI: 10.1038/sj.onc.1205821.

Peng TS, Qiu JS, Wu HX, et al., 2002, Expressions of CD44s, MMP-9, and Ki-67: Possible Association with Invasion, Metastasis, and Recurrence of Osteosarcoma. Ai Zheng, 21(7):745–50.

Chen T, Nie H, Gao X, et al., 2014, Epithelial-Mesenchymal Transition Involved in Pulmonary Fibrosis Induced by Multi-Walled Carbon Nanotubes via TGF-Beta/Smad Signaling Pathway. Toxicol Lett, 226(2):150–62. DOI: 10.1016/j. toxlet.2014.02.004.

Katsuno Y, Lamouille S, Derynck R, 2013, TGF-β Signaling and Epithelial-Mesenchymal Transition in Cancer Progression. Curr Opin Oncol, 25(1):76–84. DOI: 10.1097/ CCO.0b013e32835b6371.

Kriegel MA, Li MO, Sanjabi S, et al., 2006, Transforming Growth Factor-Beta: Recent Advances on its Role in Immune Tolerance. Curr Rheumatol Rep, 8(2):138–44. DOI: 10.1007/s11926-006-0054-y.

Huang X, Huang S, Zhang F, et al., 2010, Lentiviral-Mediated Smad4 RNAi Promotes SMMC-7721 Cell Migration by Regulation of MMP-2, VEGF and MAPK Signaling. Mol Med Rep, 3(2):295–9. DOI: 10.3892/ mmr_00000254.

Del Re E, Babitt JL, Pirani A, et al., 2004, In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)- Beta Type II-B Receptor Requires the Type I Receptor to Bind TGF-beta2. J Biol Chem, 279(21):22765–72. DOI: 10.1074/jbc.M401350200.

Suzuki H, Yagi K, Kondo M, et al., 2004, c-Ski Inhibits the TGF-Beta Signaling Pathway Through Stabilization of Inactive Smad Complexes on Smad-Binding Elements. Oncogene, 23(29):5068–76. DOI: 10.1038/sj.onc.1207690.

Hardt PD, Ewald N, 2008, Tumor M2 Pyruvate Kinase: A Tumor Marker and its Clinical Application in Gastrointestinal Malignancy. Expert Rev Mol Diagn, 8(5):579–85. DOI: 10.1586/14737159.8.5.579.

Hardt PD, Toepler M, Ngoumou B, et al., 2003, Fecal Pyruvate Kinase Concentrations (ELISA Based on a Combination of Clone 1 and Clone 3 Antibodies) for Gastric Cancer Screening. Anticancer Res, 23(2A):855–7.

Goonetilleke KS, Mason JM, Siriwardana P, 2007, Diagnostic and Prognostic Value of Plasma Tumor M2 Pyruvate Kinase in Periampullary Cancer: Evidence for a Novel Biological Marker of adverse prognosis. Pancreas, 34(3):318–24. DOI: 10.1097/MPA.0b013e31802ee9c7.

Masuo T, Okamura S, Zhang Y, 2009, Cyclosporine A Inhibits Colorectal Cancer Proliferation Probably by Regulating Expression Levels of c-Myc, p21(WAF1/ CIP1) and Proliferating Cell Nuclear Antigen. Cancer Lett, 285(1):66–72. DOI: 10.1016/j.canlet.2009.05.001.

Martinez-Balibrea E, Plasencia C, Ginés A, et al., 2009, A Proteomic Approach Links Decreased Pyruvate Kinase M2 Expression to Oxaliplatin Resistance in Patients with Colorectal Cancer and in Human Cell Lines. Mol Cancer Ther, 8(4):771–8. DOI: 10.1158/1535-7163.

Spoden GA, Mazurek S, Morandell D, et al., 2008, Isotype Specific Inhibitors of the Glycolytic Key Regulator Pyruvate Kinase Subtype M2 Moderately Decelerate Tumor Cell Proliferation. Int J Cancer, 123(2):312–21. DOI: 10.1002/ ijc.23512.

Heiden MG, Christofk HR, Schuman E, et al., 2010, Identification of Small Molecule Inhibitors of Pyruvate Kinase M2. Biochem Pharmacol, 79(8):1118–24. DOI: 10.1016/j.bcp.2009.12.003.

Boxer MB, Jiang JK, Heiden MG, et al., 2010, Evaluation of Substituted N, N’-Diarylsulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase. J Med Chem, 53(3):1048–55. DOI: 10.1021/jm901577g.

Jiang JK, Boxer MB, Heiden MG, et al., 2010, Evaluation of thieno [3, 2-b] pyrrole [3, 2-d] Pyridazinones as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase. Bioorg Med Chem Lett, 20(11):3387–93. DOI: 10.1016/j. bmcl.2010.04.015.

Walsh MJ, Brimacombe KR, Veith H, et al., 2011, 2-Oxo-N-aryl-1, 2, 3, 4-Tetrahydroquinoline-6-Sulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase. Bioorg Med Chem Lett, 21(21):6322–7. DOI: 10.1016/j.bmcl.2011.08.114




DOI: http://dx.doi.org/10.18063/ghl.v3i2.276

Refbacks

  • There are currently no refbacks.


Copyright (c) 2022 Mingyue Zhu

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Recent Articles | About Journal | For Author | Fees | About Whioce

Copyright © Whioce Publishing Pte Ltd. All Rights Reserved.