PKM2调控肿瘤细胞代谢的研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2015.06.007

摘要/Abstract

摘要： 肿瘤细胞代谢的最重要特征是消耗大量的糖并产生乳酸。M2-型丙酮酸激酶 2(PKM2)在这种代谢表型中发挥决定性的作用，体内外实验均发现 PKM2 的过表达可明显增强 Warburg 效应，促进肿瘤生长。然而关于PKM2调节肿瘤细胞代谢的机制仍然不是很清楚。当前的研究也提出了一些新颖的PKM2调节肿瘤代谢的观点。在总结当前认识的同时，提出一些本领域的未来可能的研究方向，重点突出肿瘤细胞中关于PKM2活性和特异性的争议，并对PKM2潜在的治疗策略进行讨论。

关键词: PKM2, 肿瘤细胞代谢, Warburg效应, 糖酵解

Abstract: Tumor cell metabolism is exemplified by high glucose consumption and lactate production. The M2 isoform of pyruvate kinase(PKM2)plays a vital role in this metabolic phenotype, experiments both in vitro and in vivo revealed that over-expression of PKM2 would increase the Warburg effect and promote the tumor growth. However, the mechanisms of how PKM2 regulates tumor cell metabolism are still not completely understood. Current researches have elucidated novel PKM2 regulatory mechanisms. In this review the current understanding is summarized and future directions in this field are explored, highlighting controversies regarding the activity and specificity of PKM2 in tumor. Finally, the potential therapeutic implications and strategies are discussed.

Key words: PKM2, tumor cell metabolism, Warburg effect, glycolysis

许昆, 王子迎. PKM2调控肿瘤细胞代谢的研究进展[J]. 生物技术通报, 2015, 31(6): 48-54.

Xu Kun, Wang Ziying. Research Advances on Tumor Cell Metabolism Regulated by PKM2[J]. Biotechnology Bulletin, 2015, 31(6): 48-54.

参考文献

[1] Warburg O. The metabolism of tumors in the body[J]. J Gen Physiol, 1927, 8(6)：519-530.
[2] Koppenol WH, BoundsPL, DangCV. Otto Warburg’s contributions to current concepts of cancer metabolism[J]. Nat Rev Cancer, 2011, 11(5)：325-337.
[3] Gupta V, Bamezai RN. Human pyruvate kinase M2：a multifuncti-onal protein[J]. Protein Sci, 2010, 19(11)：2031-2044.
[4] Altenberg B, Greulich KO. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes[J]. Genomics, 2004, 84：1014-1020.
[5] Baek SH. When signaling kinases meet histones and histone modifiers in the nucleus[J]. Mol Cell, 2011, 42：274-284.
[6] Warburg O. On the origin of cancer cells[J]. Science, 1956, 123：309-314.
[7] Mu?oz-Pinedo C, El Mjiyad N, Ricci JE. Cancer metabolism：current perspectives and future dire-ctions[J]. Cell Death Dis, 2012, 3：e248.
[8] Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism[J]. Nat Rev Cancer, 2011, 11：85-95.
[9] Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive[J]. Nat Cell Biol, 2004, 6(11)：1122-1128.
[10] Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics[J]. Oncogene, 2010, 29：625-634.
[11] David CJ, Chen M, Assanah M, et al. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer[J]. Nature, 2010, 463：364-368.
[12] 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 USA, 2010, 107：1894-1899.
[13]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, 19：346-335.
[14]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.
[15]Chaneton B, Gottlieb E. Rocking cell metabolism：revised functions of the key glycolytic regulator PKM2 in cancer[J]. Trends Biochem Sci, 2012, 37(8)：309-316.
[16]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)：73-75.
[17]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.
[18]Bluemlein K, Grüning NM, Feichtinger RG, et al. No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesi[J]. Oncotarget, 2011, 2：393-400.
[19]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.
[20]Keller KE, Tan IS, LeeYS. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions[J]. Science, 2012, 338(6110)：1069-1072.
[21]Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology[J]. Semin Cell Dev Biol, 2012, 23(4)：352-361.
[22]Sun Y, Connors KE, Yang DQ. AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner[J]. Mol Cell Biochem, 2007, 306(12)：239-245.
[23]Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo[J]. Cell Metabolism, 2013, 17(1)：113-124.
[24]Yoo YG, Hayashi M, Christensen J, Huang LE. An essential role of the HIF-1alpha-c-Myc axis in malignant progression[J]. Ann N Y Acad Sci, 2009, 1177：198-204.
[25]Lu Z. Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis[J]. Chin J Cancer, 2012, 31(1)：5-7.
[26]Steták A, Veress R, Ovádi J, et al. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death[J]. Cancer Res, 2007, 67(4)：1602-1608.
[27] Dombrauckas JD, Santarsiero BD, Mesecar AD. Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis[J]. Biochemistry, 2005, 44：9417-9429.
[28]Lv L, Li D, Zhao D, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth[J]. Mol Cell, 2011, 42(6)：719-730.
[29]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.
[30]Weibo L, Gregg LS. 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.
[31]Lee J, Kim HK, Han YM, Kim J, et al. Pyruvate kinase isozyme type M2 . PKM2)interacts and cooperates with Oct-4 in regulating transcription[J]. Int J Biochem Cell Biol, 2008, 40(5)：1043-1054.
[32]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.
[33]Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancer by oncogenes and tumor suppressor genes[J]. Science, 2010, 330：1340-1344.
[34]Carroll RC, Ash JF, Vogt PK, Singer SJ. Reversion of transformed glycolysis to normal by inhibition of protein synthesis in rat kidney cells infected with temperature-sensitive mutant of Rous sarcoma virus[J]. Proc Natl Acad Sci USA, 1978, 75：5015-5019.
[35]Lunt SY, Vander Heiden MG. Aerobic glycolysis：meeting the metabolic requireements of cell proliferation[J]. Annu Rev Cell Dev Biol, 2011, 27：441-464.
[36]Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate：a metabolic key player in cancer[J]. Cancer Res, 2011, 71：6921-6925.
[37]Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics[J]. Oncogene, 2010, 29：625-634.
[38]Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation[J]. Mol Cell Biol, 1992, 12：5447-5454.
[39]Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation[J]. Cell, 2001, 107：43-54.
[40] Yang W, Zheng Y, Xia Y, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect[J]. Nat Cell Biol, 2012, 14(12)：1295-1304.
[41]Yang W, Xia Y, Ji H, et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation[J]. Nature, 2011, 480(7375)：118-122.
[42]Yang W, Xia Y, Hawke D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis[J]. Cell, 2012, 150(4)：685-696.
[43]Semenza GL. HIF-1：upstream and downstream of cancer metabolism[J]. Curr Opin Genet Dev, 2010, 20(1)：51-56.
[44]Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma[J]. J. Bioenerg Biomembr, 2007, 39：231-234.
[45]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.
[46]Spoden GA, Mazurek S, Morandell D, et al . Isotype-specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation[J]. Int J Cancer, 2008, 123：312-321.
[47]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, 30：4297-4306.
[48]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, 452：230-233.