M2型丙酮酸激酶在肿瘤代谢中的作用

doi:10.3760/cma.j.issn.1673422X.2014.01.006

摘要/Abstract

摘要： M2型丙酮酸激酶（PKM2）是糖酵解途径的一个关键限速酶，在多种恶性肿瘤细胞中高表达。在肿瘤糖代谢通路中，PKM2可以通过在高活性的四聚体和低活性的二聚体之间相互转化，促进肿瘤的糖酵解和细胞增殖。肿瘤细胞通过多种方式调节PKM2的表达和酶活性如转录调节、变构调节和翻译后修饰调节。PKM2在肿瘤发生和肿瘤代谢中的重要作用使它有望成为肿瘤治疗的新靶点。

关键词: 丙酮酸激酶, 肿瘤, 糖酵解, M2型丙酮酸激酶

Abstract: The M2type of pyruvate kinase (PKM2) is a key ratelimiting enzyme in glycolytic pathway, and is highly expressed in diverse tumor cells. In glycometabolism pathway of tumor, PKM2 can promote glycolysis and tumor cells growth through the mutual transformation between highly active tetramer and lowly active dimer. Tumor cells can regulate PKM2 expression and enzymatic activity through many mechanisms, such as transcription regulation, allosteric regulation and posttranslational modification. PKM2 is expected to be a new target for oncotherapy because of its vital function in tumorigenesis and tumor metabolism.

Key words: Pyruvate kinase, Neoplasms, Glycolysis, M2type pyruvate kinase

王娟, 程斌. M2型丙酮酸激酶在肿瘤代谢中的作用[J]. 国际肿瘤学杂志, 2014, 41(1): 17-20.

Wang Juan, Cheng Bin. Role of M2type pyruvate kinase in the metabolism of tumor[J]. Journal of International Oncology, 2014, 41(1): 17-20.

参考文献

［1］ Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation［J］. Cell, 2011, 144(5): 646674. ［2］ 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. ［3］ David CJ, Chen M, Assanah M, et al. HnRNP proteins controlled by cMyc deregulate pyruvate kinase mRNA splicing in cancer［J］. Nature, 2010, 463(7279):364368. ［4］ Kwon OH, Kang TW, Kim JH, et al. Pyruvate kinase M2 promotes the growth of gastric cancer cells via regulation of BclxL expression at transcriptional level［J］. Biochem Biophys Res Commun, 2012, 423(1):3844. ［5］ Zhou CF, Li XB, Sun H, et al. Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells［J］. IUBMB Life, 2012, 64(9):775782. ［6］ Novotn I, Dítě P, Dastych M, et al. Tumor marker M2pyruvatekinase in differential diagnosis of chronic pancreatitis and pancreatic cancer［J］. Hepatogastroenterology, 2008, 55(85):14751477. ［7］ Landt S, Jeschke S, Koeninger A, et al. Tumorspecific correlation of tumor M2 pyruvate kinase in preinvasive, invasive and recurrent cervical cancer［J］. Anticancer Res, 2010, 30(2):375381. ［8］ Wong TS, Liu XB, ChungWai Ho A, et al. Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling［J］. Int J Cancer, 2008, 123(2):251257. ［9］ Ervens J, Fuchs H, Niemann VT, et al. Pyruvate kinase isoenzyme M2 is not of diagnostic relevance as a marker for oral cancer［J］. J Craniomaxillofac Surg, 2008, 36(2):8994. ［10］ 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. ［11］ Jung Y, Jang YJ, Kang MH, et al. Metabolic signature genes associated with susceptibility to pyruvate kinase, muscle type 2 gene ablation in cancer cells［J］. Mol Cells, 2013, 35(4):335341. ［12］ Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxiainducible factor 1 in cancer cells［J］. Oncotarget, 2011, 2(7):551556. ［13］ Luo W, Hu H, Chang R, et al. Pyruvate kinase M2 is a PHD3stimulated coactivator for hypoxiainducible factor 1［J］. Cell, 2011, 145(5):732744. ［14］ Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism［J］. Nat Rev Cancer, 2011, 11(2):8595. ［15］ Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression［J］. Trends Endocrinol Metab, 2012, 23(11):560566. ［16］ Tamada M, Suematsu M, Saya H. Pyruvate kinase M2: multiple faces for conferring benefits on cancer cells［J］. Clin Cancer Res, 2012, 18(20):55545561. ［17］ 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. ［18］ 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):ra73. ［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 Q, Zhang Y, Yang C, et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux［J］. Science, 2010, 327(5968):10041007. ［21］ 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 USA, 2011, 108(10):41294134. ［22］ Hoshino A, Hirst JA, Fujii H. Regulation of cell proliferation by interleukin3induced nuclear translocation of pyruvate kinase［J］. J Biol Chem, 2007, 282(24):1770617711. ［23］ Yang W, Xia Y, Ji H, et al. Nuclear PKM2 regulates betacatenin transactivation upon EGFR activation［J］. Nature, 2011, 480(7375):118122. ［24］ 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. ［25］ Vander Heiden MG, Christofk HR, Schuman E, et al. Identification of small molecule inhibitors of pyruvate kinase M2［J］. Biochem Pharmacol, 2010, 79(8):11181124. ［26］ Chen J, Xie J, Jiang Z, et al. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinaseM2［J］. Oncogene, 2011, 30(42):42974306. ［27］ Goldberg MS, Sharp PA. Pyruvate kinase M2specific siRNA induces apoptosis and tumor regression［J］. J Exp Med, 2012, 209(2):217224.

[1]	刘娜, 寇介丽, 杨枫, 刘桃桃, 李丹萍, 韩君蕊, 杨立洲. 血清miR-106b-5p、miR-760联合低剂量螺旋CT诊断早期肺癌的临床价值[J]. 国际肿瘤学杂志, 2024, 51(6): 321-325.
[2]	杨蜜, 别俊, 张加勇, 邓佳秀, 唐组阁, 卢俊. 局部晚期可切除食管癌新辅助治疗疗效及预后分析[J]. 国际肿瘤学杂志, 2024, 51(6): 332-337.
[3]	袁健, 黄燕华. Hp-IgG抗体联合血清DKK1、sB7-H3对早期胃癌的诊断价值[J]. 国际肿瘤学杂志, 2024, 51(6): 338-343.
[4]	陈红健, 张素青. 血清miR-24-3p、H2AFX与肝癌患者临床病理特征及术后复发的关系研究[J]. 国际肿瘤学杂志, 2024, 51(6): 344-349.
[5]	郭泽浩, 张俊旺. PFDN及其亚基在肿瘤发生发展中的作用[J]. 国际肿瘤学杂志, 2024, 51(6): 350-353.
[6]	张百红, 岳红云. 新作用机制的抗肿瘤药物进展[J]. 国际肿瘤学杂志, 2024, 51(6): 354-358.
[7]	许凤琳, 吴刚. EBV在鼻咽癌肿瘤免疫微环境和免疫治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 359-363.
[8]	王盈, 刘楠, 郭兵. 抗体药物偶联物在转移性乳腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 364-369.
[9]	张蕊, 褚衍六. 基于FIT与肠道菌群的结直肠癌风险评估模型的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 370-375.
[10]	高凡, 王萍, 杜超, 褚衍六. 肠道菌群与结直肠癌非手术治疗的相关研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 376-381.
[11]	王丽, 刘志华, 杨伟洪, 蒋凤莲, 李全泳, 宋浩杰, 鞠文东. ROS1突变肺腺鳞癌合并脑梗死为主要表现的Trousseau综合征1例[J]. 国际肿瘤学杂志, 2024, 51(6): 382-384.
[12]	刘静, 刘芹, 黄梅. 基于SMOTE算法的食管癌放化疗患者肺部感染的预后模型构建[J]. 国际肿瘤学杂志, 2024, 51(5): 267-273.
[13]	杨琳, 路宁, 温华, 张明鑫, 朱琳. 炎症负荷指数与胃癌临床关系研究[J]. 国际肿瘤学杂志, 2024, 51(5): 274-279.
[14]	王俊毅, 洪楷彬, 纪荣佳, 陈大朝. 癌结节对结直肠癌根治性切除术后肝转移的影响[J]. 国际肿瘤学杂志, 2024, 51(5): 280-285.
[15]	张宁宁, 杨哲, 檀丽梅, 李振宁, 王迪, 魏永志. 宫颈细胞DNA倍体分析联合B7-H4和PKCδ对宫颈癌的诊断价值[J]. 国际肿瘤学杂志, 2024, 51(5): 286-291.