M2型丙酮酸激酶的抗肿瘤作用研究进展
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摘要
糖酵解(Warburg效应)是肿瘤细胞的重要特征,其相比于线粒体氧化磷酸化来说更高效地产生能量及大量的中间产物用于生物合成,还可抑制活性氧的生成。M2型丙酮酸激酶(pyruvate kinase M2,PKM2)多以低活性的二聚体形式存在于肿瘤细胞等快速增殖细胞中,作为催化糖酵解最后一个步骤的限速酶,是肿瘤细胞Warburg效应的一个关键调节因子。PKM2在肿瘤细胞中也发挥着重要的非代谢作用。PKM2被诱导转移入细胞核后,通过磷酸化特定的核蛋白后激活诸多基因的转录,促进肿瘤的生长。基于这些研究成果,该文综述了PKM2在肿瘤生长中的作用,并对PKM2的抑制剂和激活剂的抗肿瘤疗效分别进行讨论,并预测PKM2可能成为癌症治疗的潜在靶点。
Glycolysis (Warburg effect) is an important metabolic feature of tumor cells. Compared with mitochondrial oxidative phosphorylation,glycolysis promotes rapid energy production and a great number of glycolytic intermediates for biosynthesis without the accumulation of reactive oxygen species. Pyruvate kinase M2(PKM2) is expressed in proliferative cells and cancer cells. The predominant form of PKM2 is the dimer with lower activity. It is the rate-limiting enzyme of the last step of glycolysis and the critical regulatory factor of aerobic glycolysis. PKM2 also plays an important role in non-glycolytic functions. After translocating to nucleus,PKM2 phosphorylates specific nucleoproteins and activates the transcription of related genes to promote tumor growth. This article reviews the role of PKM2 in tumor cell growth,the anticancer effects of PKM2 activators and inhibitors,and explores the possibility of PKM2 as a potential target for cancer treatment.
Glycolysis (Warburg effect) is an important metabolic feature of tumor cells. Compared with mitochondrial oxidative phosphorylation,glycolysis promotes rapid energy production and a great number of glycolytic intermediates for biosynthesis without the accumulation of reactive oxygen species. Pyruvate kinase M2(PKM2) is expressed in proliferative cells and cancer cells. The predominant form of PKM2 is the dimer with lower activity. It is the rate-limiting enzyme of the last step of glycolysis and the critical regulatory factor of aerobic glycolysis. PKM2 also plays an important role in non-glycolytic functions. After translocating to nucleus,PKM2 phosphorylates specific nucleoproteins and activates the transcription of related genes to promote tumor growth. This article reviews the role of PKM2 in tumor cell growth,the anticancer effects of PKM2 activators and inhibitors,and explores the possibility of PKM2 as a potential target for cancer treatment.
引文
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[3]Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation[J].Science,2009,324(5930):1029-1033.
[4]Iansante V,Choy PM,Fung SW,et al.PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation[J].Nat Commun,2015,6:7882.
[5]Clower CV,Chatterjee D,Wang Z,et al.The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism[J].Proc Natl Acad Sci U S A,2010,107(5):1894-1899.
[6]David CJ,Chen M,Assanah M,et al.HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNAsplicing in cancer[J].Nature,2010,463(7279):364-368.
[7]Cairns RA,Harris IS,Mak TW.Regulation of cancer cell metabolism[J].Nat Rev Cancer,2011,11(2):85-95.
[8]Hsu MC,Hung WC.Pyruvate kinase M2 fuels multiple aspects of cancer cells:from cellular metabolism,transcriptional regulation to extracellular signaling[J].Mol Cancer,2018,17(1):35.
[9]Chen M,David CJ,Manley JL.Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins[J].Nat Struct Mol Biol,2012,19(3):346-354.
[10]Luo W,Hu H,Chang R,et al.Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor1[J].Cell,2011,145(5):732-744.
[11]Panasyuk G,Espeillac C,Chauvin C,et al.PPARgamma contributes to PKM2 and HK2 expression in fatty liver[J].Nat Commun,2012,3:672.
[12]Sun Q,Chen X,Ma J,et al.Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth[J].Proc Natl Acad Sci U S A,2011,108(10):4129-4134.
[13]Shang Y,He J,Wang Y,et al.CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma[J].Oncogene,2017,36(29):4191-4200.
[14]Li W,Liu J,Zhao Y.PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells[J].Mol Carcinog,2014,53(5):403-412.
[15]Hitosugi T,Kang S,Vander Heiden MG,et al.Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth[J].Sci Signal,2009,2(97):73.
[16]Ye J,Mancuso A,Tong X,et al.Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation[J].Proc Natl Acad Sci U S A,2012,109(18):6904-6909.
[17]Christofk HR,Vander Heiden MG,Wu N,et al.Pyruvate kinase M2 is a phosphotyrosine-binding protein[J].Nature,2008,452(7184):181-186.
[18]Nakatsu D,Horiuchi Y,Kano F,et al.L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2[J].Proc Natl Acad Sci U S A,2015,112(10):1067-1076.
[19]Anastasiou D,Poulogiannis G,Asara JM,et al.Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses[J].Science,2011,334(6060):1278-1283.
[20]Wang P,Sun C,Zhu T,Xu Y.Structural insight into mechanisms for dynamic regulation of PKM2[J].Protein Cell,2015,6(4):275-287.
[21]Wu X,Zhou Y,Zhang K,et al.Isoform-specific interaction of pyruvate kinase with hepatitis C virus NS5B[J].FEBSLett,2008,582(15):2155-2160.
[22]Gao X,Wang H,Yang JJ,et al.Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase[J].Mol Cell,2012,45(5):598-609.
[23]Yang W,Xia Y,Ji H,et al.Nuclear PKM2 regulates betacatenin transactivation upon EGFR activation[J].Nature,2011,480(7375):118-122.
[24]Lv L,Xu YP,Zhao D,et al.Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization[J].Mol Cell,2013,52(3):340-352.
[25]Munoz-Pinedo C,El Mjiyad N,Ricci JE.Cancer metabolism:current perspectives and future directions[J].Cell Death Dis,2012,3:248.
[26]Kung C,Hixon J,Choe S,et al.Small molecule activation of PKM2 in cancer cells induces serine auxotrophy[J].Chem Biol,2012,19(9):1187-1198.
[27]Anastasiou D,Yu Y,Israelsen WJ,et al.Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis[J].Nat Chem Biol,2012,8(10):839-847.
[28]Chaneton B,Hillmann P,Zheng L,et al.Serine is a natural ligand and allosteric activator of pyruvate kinase M2[J].Nature,2012,491(7424):458-462.
[29]Boxer MB,Jiang JK,Vander Heiden MG,et al.Evaluation of substituted N,N'-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase[J].JMed Chem,2010,53(3):1048-1055.
[30]Xu Y,Liu XH,Saunders M,et al.Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2isoform of pyruvate kinase(PKM2)[J].Bioorg Med Chem Lett,2014,24(2):515-519.
[31]Aslan E,Guler C,Adem S.In vitro effects of some flavonoids and phenolic acids on human pyruvate kinase isoenzyme M2[J].J Enzyme Inhib Med Chem,2016,31(2):314-317.
[32]Guo C,Linton A,Jalaie M,et al.Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators[J].Bioorg Med Chem Lett,2013,23(11):3358-3363.
[33]Azoitei N,Becher A,Steinestel K,et al.PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation[J].Mol Cancer,2016,15:3.
[34]Yang L,Xie M,Yang M,et al.PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis[J].Nat Commun,2014,5:4436.
[35]Sun H,Zhu A,Zhang L,et al.Knockdown of PKM2 suppresses tumor growth and invasion in lung adenocarcinoma[J].Int J Mol Sci,2015,16(10):24574-24587.
[36]Yuan S,Qiao T,Zhuang X,et al.Knockdown of the M2isoform of pyruvate kinase(PKM2)with shRNA enhances the effect of docetaxel in human NSCLC cell lines in vitro[J].Yonsei Med J,2016,57(6):1312-1323.
[37]Ao R,Guan L,Wang Y,et al.Effects of PKM2 gene silencing on the proliferation and apoptosis of colorectal cancer LS-147T and SW620 cells[J].Cell Physiol Biochem,2017,42(5):1769-1778.
[38]Wang Y,Hao F,Nan Y,et al.PKM2 inhibitor shikonin overcomes the cisplatin resistance in bladder cancer by inducing necroptosis[J].Int J Biol Sci,2018,14(13):1883-1891.
[39]Shen Y,Chen M,Huang S,et al.Pantoprazole inhibits human gastric adenocarcinoma SGC-7901 cells by downregulating the expression of pyruvate kinase M2[J].Oncol Lett,2016,11(1):717-722.
[40]Chen J,Jiang Z,Wang B,et al.Vitamin K(3)and K(5)are inhibitors of tumor pyruvate kinase M2[J].Cancer Lett,2012,316(2):204-210.
[41]Chen G,Feng W,Zhang S,et al.Metformin inhibits gastric cancer via the inhibition of HIF1alpha/PKM2 signaling[J].Am J Cancer Res,2015,5(4):1423-1434.
[42]Zhang C,Hu J,Sheng L,et al.Metformin delays AKT/cMet-driven hepatocarcinogenesis by regulating signaling pathways for de novo lipogenesis and ATP generation[J].Toxicol Appl Pharmacol,2019,365:51-60.
[43]Dando I,Donadelli M,Costanzo C,et al.Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells[J].Cell Death Dis,2013,4:664.
[44]Masuo T,Okamura S,Zhang Y,et al.Cyclosporine A inhibits colorectal cancer proliferation probably by regulating expression levels of c-Myc,p21(WAF1/CIP1)and proliferating cell nuclear antigen[J].Cancer Lett,2009,285(1):66-72.
[45]Liu J,Wu N,Ma L,et al.Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms[J].PLoS One,2014,9(3):91606.
[2]Christofk HR,Vander Heiden MG,Harris MH,et al.The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth[J].Nature,2008,452(7184):230-233.
[3]Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation[J].Science,2009,324(5930):1029-1033.
[4]Iansante V,Choy PM,Fung SW,et al.PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation[J].Nat Commun,2015,6:7882.
[5]Clower CV,Chatterjee D,Wang Z,et al.The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism[J].Proc Natl Acad Sci U S A,2010,107(5):1894-1899.
[6]David CJ,Chen M,Assanah M,et al.HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNAsplicing in cancer[J].Nature,2010,463(7279):364-368.
[7]Cairns RA,Harris IS,Mak TW.Regulation of cancer cell metabolism[J].Nat Rev Cancer,2011,11(2):85-95.
[8]Hsu MC,Hung WC.Pyruvate kinase M2 fuels multiple aspects of cancer cells:from cellular metabolism,transcriptional regulation to extracellular signaling[J].Mol Cancer,2018,17(1):35.
[9]Chen M,David CJ,Manley JL.Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins[J].Nat Struct Mol Biol,2012,19(3):346-354.
[10]Luo W,Hu H,Chang R,et al.Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor1[J].Cell,2011,145(5):732-744.
[11]Panasyuk G,Espeillac C,Chauvin C,et al.PPARgamma contributes to PKM2 and HK2 expression in fatty liver[J].Nat Commun,2012,3:672.
[12]Sun Q,Chen X,Ma J,et al.Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth[J].Proc Natl Acad Sci U S A,2011,108(10):4129-4134.
[13]Shang Y,He J,Wang Y,et al.CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma[J].Oncogene,2017,36(29):4191-4200.
[14]Li W,Liu J,Zhao Y.PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells[J].Mol Carcinog,2014,53(5):403-412.
[15]Hitosugi T,Kang S,Vander Heiden MG,et al.Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth[J].Sci Signal,2009,2(97):73.
[16]Ye J,Mancuso A,Tong X,et al.Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation[J].Proc Natl Acad Sci U S A,2012,109(18):6904-6909.
[17]Christofk HR,Vander Heiden MG,Wu N,et al.Pyruvate kinase M2 is a phosphotyrosine-binding protein[J].Nature,2008,452(7184):181-186.
[18]Nakatsu D,Horiuchi Y,Kano F,et al.L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2[J].Proc Natl Acad Sci U S A,2015,112(10):1067-1076.
[19]Anastasiou D,Poulogiannis G,Asara JM,et al.Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses[J].Science,2011,334(6060):1278-1283.
[20]Wang P,Sun C,Zhu T,Xu Y.Structural insight into mechanisms for dynamic regulation of PKM2[J].Protein Cell,2015,6(4):275-287.
[21]Wu X,Zhou Y,Zhang K,et al.Isoform-specific interaction of pyruvate kinase with hepatitis C virus NS5B[J].FEBSLett,2008,582(15):2155-2160.
[22]Gao X,Wang H,Yang JJ,et al.Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase[J].Mol Cell,2012,45(5):598-609.
[23]Yang W,Xia Y,Ji H,et al.Nuclear PKM2 regulates betacatenin transactivation upon EGFR activation[J].Nature,2011,480(7375):118-122.
[24]Lv L,Xu YP,Zhao D,et al.Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization[J].Mol Cell,2013,52(3):340-352.
[25]Munoz-Pinedo C,El Mjiyad N,Ricci JE.Cancer metabolism:current perspectives and future directions[J].Cell Death Dis,2012,3:248.
[26]Kung C,Hixon J,Choe S,et al.Small molecule activation of PKM2 in cancer cells induces serine auxotrophy[J].Chem Biol,2012,19(9):1187-1198.
[27]Anastasiou D,Yu Y,Israelsen WJ,et al.Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis[J].Nat Chem Biol,2012,8(10):839-847.
[28]Chaneton B,Hillmann P,Zheng L,et al.Serine is a natural ligand and allosteric activator of pyruvate kinase M2[J].Nature,2012,491(7424):458-462.
[29]Boxer MB,Jiang JK,Vander Heiden MG,et al.Evaluation of substituted N,N'-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase[J].JMed Chem,2010,53(3):1048-1055.
[30]Xu Y,Liu XH,Saunders M,et al.Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2isoform of pyruvate kinase(PKM2)[J].Bioorg Med Chem Lett,2014,24(2):515-519.
[31]Aslan E,Guler C,Adem S.In vitro effects of some flavonoids and phenolic acids on human pyruvate kinase isoenzyme M2[J].J Enzyme Inhib Med Chem,2016,31(2):314-317.
[32]Guo C,Linton A,Jalaie M,et al.Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators[J].Bioorg Med Chem Lett,2013,23(11):3358-3363.
[33]Azoitei N,Becher A,Steinestel K,et al.PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation[J].Mol Cancer,2016,15:3.
[34]Yang L,Xie M,Yang M,et al.PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis[J].Nat Commun,2014,5:4436.
[35]Sun H,Zhu A,Zhang L,et al.Knockdown of PKM2 suppresses tumor growth and invasion in lung adenocarcinoma[J].Int J Mol Sci,2015,16(10):24574-24587.
[36]Yuan S,Qiao T,Zhuang X,et al.Knockdown of the M2isoform of pyruvate kinase(PKM2)with shRNA enhances the effect of docetaxel in human NSCLC cell lines in vitro[J].Yonsei Med J,2016,57(6):1312-1323.
[37]Ao R,Guan L,Wang Y,et al.Effects of PKM2 gene silencing on the proliferation and apoptosis of colorectal cancer LS-147T and SW620 cells[J].Cell Physiol Biochem,2017,42(5):1769-1778.
[38]Wang Y,Hao F,Nan Y,et al.PKM2 inhibitor shikonin overcomes the cisplatin resistance in bladder cancer by inducing necroptosis[J].Int J Biol Sci,2018,14(13):1883-1891.
[39]Shen Y,Chen M,Huang S,et al.Pantoprazole inhibits human gastric adenocarcinoma SGC-7901 cells by downregulating the expression of pyruvate kinase M2[J].Oncol Lett,2016,11(1):717-722.
[40]Chen J,Jiang Z,Wang B,et al.Vitamin K(3)and K(5)are inhibitors of tumor pyruvate kinase M2[J].Cancer Lett,2012,316(2):204-210.
[41]Chen G,Feng W,Zhang S,et al.Metformin inhibits gastric cancer via the inhibition of HIF1alpha/PKM2 signaling[J].Am J Cancer Res,2015,5(4):1423-1434.
[42]Zhang C,Hu J,Sheng L,et al.Metformin delays AKT/cMet-driven hepatocarcinogenesis by regulating signaling pathways for de novo lipogenesis and ATP generation[J].Toxicol Appl Pharmacol,2019,365:51-60.
[43]Dando I,Donadelli M,Costanzo C,et al.Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells[J].Cell Death Dis,2013,4:664.
[44]Masuo T,Okamura S,Zhang Y,et al.Cyclosporine A inhibits colorectal cancer proliferation probably by regulating expression levels of c-Myc,p21(WAF1/CIP1)and proliferating cell nuclear antigen[J].Cancer Lett,2009,285(1):66-72.
[45]Liu J,Wu N,Ma L,et al.Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms[J].PLoS One,2014,9(3):91606.