PKM2 and cancer: The function of PKM2 beyond glycolysis (Review)

Oncology Letters

Volumn 11, Issue 3, 2016, Pages 1980-1986

  Dong, Gaochao ^a   Mao, Qixing ^a,b   Xia, Wenjie ^a,b   Xu, Youtao ^a,b   Wang, Jie ^a   Xu, Lin ^a   Jiang, Feng ^a  

^a JIANGSU CANCER HOSPITAL   (China)

^b NANJING MEDICAL UNIVERSITY   (China)

Author keywords

Cancer; Glycolysis; Metabolic reprogramming; Novel function; PKM2; Warburg effect

Indexed keywords

ADENOSINE TRIPHOSPHATE; BETA CATENIN; CYCLIN D1; EPIDERMAL GROWTH FACTOR RECEPTOR; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; HISTONE DEACETYLASE 3; HYPOXIA INDUCIBLE FACTOR 1ALPHA; I KAPPA B KINASE BETA; I KAPPA B KINASE GAMMA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; OLEANOLIC ACID; PHOSPHATIDYLINOSITIDE; PROTEIN E7; PROTEIN KINASE C; PYRUVATE KINASE; PYRUVATE KINASE MUSCLE ISOZYME M2; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; RETINOBLASTOMA BINDING PROTEIN 2; RING FINGER PROTEIN; SERINE ARGININE RICH SPLICING FACTOR; STAT3 PROTEIN; TYROSINE; UNCLASSIFIED DRUG;

CANCER GROWTH; CARCINOGENESIS; CELL PROLIFERATION; CIRCULATION; ENZYME ACTIVITY; EXON; GENE; GENE CONTROL; GENE OVEREXPRESSION; GLYCOLYSIS; HUMAN; MISSENSE MUTATION; NEOPLASM; PKM2 GENE; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS REGULATION; REVIEW; RNA SPLICING; SIGNAL TRANSDUCTION; UPREGULATION;

EID: 84958073577     PISSN: 17921074     EISSN: 17921082     Source Type: Journal    
DOI: 10.3892/ol.2016.4168     Document Type: Review

References (59)

1. Warburg O, Wind F and Negelein E: The metabolism of tumors in the body. J Gen Physiol 8: 519-530, 1927.
2. Warburg O: On the origin of cancer cells. Science 123: 309-314, 1956.
3. Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell 144: 646-674, 2011.
4. Hsu PP and Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell 134: 703-707, 2008.
5. Gambhir SS: Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2: 683-693, 2002.
6. Mathupala SP, Rempel A and 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 276: 43407-43412, 2001.
7. Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324: 1029-1033, 2009.
8. Altenberg B and Greulich KO: Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84: 1014-1020, 2004.
9. Noguchi T, Inoue H and Tanaka T: The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem 261: 13807-13812, 1986.
10. Noguchi T, Yamada K, Inoue H, Matsuda T and Tanaka T: The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J Biol Chem 262: 14366-14371, 1987.
11. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL and Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: 230-233, 2008.
12. Yang W and Lu Z: Nuclear PKM2 regulates the Warburg effect. Cell Cycle 12: 3154-3158, 2013.
13. David CJ, Chen M, Assanah M, Canoll P and Manley JL: HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463: 364-368, 2010.
14. Wang Z, Chatterjee D, Jeon HY, Akerman M, Vander Heiden MG, Cantley LC and Krainer AR: Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J Mol Cell Biol 4: 79-87, 2012.
15. DeBerardinis RJ, Lum JJ, Hatzivassiliou G and Thompson CB: The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11-20, 2008.
16. Semenza GL: HIF-1: Upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20: 51-56, 2010.
17. Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, et al: Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 108: 4129-4134, 2011.
18. Iqbal MA, Siddiqui FA, Gupta V, Chattopadhyay S, Gopinath P, Kumar B, Manvati S, Chaman N and Bamezai RN: Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer 12: 72, 2013.
19. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A and Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145: 732-744, 2011.
20. Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, You MJ, Koh MY, Cote G, Aldape K, et al: EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell 48: 771-784, 2012.
21. Breitkreutz D, Braiman-Wiksman L, Daum N, Denning MF and Tennenbaum T: Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium. J Canc Res Clin Oncol 133: 793-808, 2007.
22. Choi JH, Ryu SH and Suh PG: On/off-regulation of phospholipase C-gamma 1-mediated signal transduction. Adv Enzyme Regul 47: 104-116, 2007.
23. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, et al: Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8: 839-847, 2012.
24. Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH, et al: Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491: 458-462, 2012.
25. Keller KE, Tan IS and Lee YS: SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science 338: 1069-1072, 2012.
26. Keller KE, Doctor ZM, Dwyer ZW and Lee YS: SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol Cell 53: 700-709, 2014.
27. Gui DY, Lewis CA and Vander Heiden MG: Allosteric regulation of PKM2 allows cellular adaptation to different physiological states. Sci Signal 6: 7, 2013.
28. Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, et al: Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334: 1278-1283, 2011.
29. Iqbal MA, Siddiqui FA, Chaman N, Gupta V, Kumar B, Gopinath P and Bamezai RN: Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner. J Biol Chem 289: 8098-8105, 2014.
30. Luo W and Semenza GL: Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2: 551-556, 2011.
31. Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung HJ and Wang WC: JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci USA 111: 279-284, 2014.
32. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, Gao X, Aldape K and Lu Z: Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480: 118-122, 2011.
33. Wu H, Li Z, Yang P, Zhang L and Fan Y: PKM2 depletion induces the compensation of glutaminolysis through β-catenin/c-Myc pathway in tumor cells. Cell Signal 26: 2397-2405, 2014.
34. Li Z, Li X, Wu S, Xue M and Chen W: Long non-coding RNA UCA1 promotes glycolysis by upregulating hexokinase 2 through the mTOR-STAT3/microRNA143 pathway. Cancer Sci 105: 951-955, 2014.
35. Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, Jiang Y, Zhou X, Li TT, Guan KL, et al: Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell 52: 340-352, 2013.
36. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC and Lu Z: ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14: 1295-1304, 2012.
37. Gao X, Wang H, Yang JJ, Liu X and Liu ZR: Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell 45: 598-609, 2012.
38. Yang P, Li Z, Fu R, Wu H and Li Z: Pyruvate kinase M2 facilitates colon cancer cell migration via the modulation of STAT3 signalling. Cell Signal 26: 1853-1862, 2014.
39. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Alfred Yung WK and Lu Z: PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150: 685-696, 2012.
40. Morfouace M, Lalier L, Oliver L, Cheray M, Pecqueur C, Cartron PF and Vallette FM: Control of glioma cell death and differentiation by PKM2-Oct4 interaction. Cell Death Dis 5: 1036, 2014.
41. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, et al: A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11: 37-51, 2007.
42. Weinberger R, Appel B, Stein A, Metz Y, Neheman A and Barak M: The pyruvate kinase isoenzyme M2 (Tu M2-PK) as a tumour marker for renal cell carcinoma. Eur J Cancer Care (Engl) 16: 333-337, 2007.
43. Ahmed AS, Dew T, Lawton FG, Papadopoulos AJ, Devaja O, Raju KS and Sherwood RA: M2-PK as a novel marker in ovarian cancer. A prospective cohort study. Eur J Gynaecol Oncol 28: 83-88, 2007.
44. Li L, Zhang Y, Qiao J, Yang JJ and Liu ZR: Pyruvate kinase M2 in blood circulation facilitates tumor growth by promoting angiogenesis. J Biol Chem 289: 25812-25821, 2014.
45. Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EE, Xian J and Cantley LC: Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol 79: 1118-1124, 2010.
46. Chen J, Xie J, Jiang Z, Wang B, Wang Y and Hu X: Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene 30: 4297-4306, 2011.
47. Goldberg MS and Sharp PA: Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med 209: 217-224, 2012.
48. Spoden GA, Rostek U, Lechner S, Mitterberger M, Mazurek S and Zwerschke W: Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell size and apoptotic cell death dependent on glucose supply. Exp Cell Res 315: 2765-2774, 2009.
49. Kung C, Hixon J, Choe S, Marks K, Gross S, Murphy E, DeLaBarre B, Cianchetta G, Sethumadhavan S, Wang X, et al: Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem Biol 19: 1187-1198, 2012.
50. Yacovan A, Ozeri R, Kehat T, Mirilashvili S, Sherman D, Aizikovich A, Shitrit A, Ben-Zeev E, Schutz N, Bohana-Kashtan O, et al: 1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg Med Chem Lett 22: 6460-6468, 2012.
51. Guo C, Linton A, Jalaie M, Kephart S, Ornelas M, Pairish M, Greasley S, Richardson P, Maegley K, Hickey 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. Bioorg Med Chem Lett 23: 3358-3363, 2013.
52. Parnell KM, Foulks JM, Nix RN, Clifford A, Bullough J, Luo B, Senina A, Vollmer D, Liu J, McCarthy V, et al: Pharmacologic activation of PKM2 slows lung tumor xenograft growth. Mol Cancer Ther 12: 1453-1460, 2013.
53. Xu Y, Liu XH, Saunders M, Pearce S, Foulks JM, Parnell KM, Clifford A, Nix RN, Bullough J, Hendrickson TF, et al: Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2 isoform of pyruvate kinase (PKM2). Bioorg Med Chem Lett 24: 515-519, 2014.
54. Liu J, Wu N, Ma L, Liu M, Liu G, Zhang Y and Lin X: Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms. PLoS One 9: 91606, 2014.
55. Vaupel P: Metabolic microenvironment of tumor cells: A key factor in malignant progression. Exp Oncol 32: 125-127, 2010.
56. Wong N, Yan J, Ojo D, De Melo J, Cutz JC and Tang D: Changes in PKM2 associate with prostate cancer progression. Cancer Invest 32: 330-338, 2014.
57. Zhan C, Shi Y, Lu C and Wang Q: Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer. Dis Esophagus 26: 746-753, 2013.
58. Zhou CF, Li XB, Sun H, Zhang B, Han YS, Jiang Y, Zhuang QL, Fang J and Wu GH: Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells. IUBMB Life 64: 775-782, 2012.
59. Warner SL, Carpenter KJ and Bearss DJ: Activators of PKM2 in cancer metabolism. Future Med Chem 6: 1167-1178, 2014.