Pyruvate kinase M2: A potential target for regulating inflammation

Frontiers in Immunology

Volumn 7, Issue APR, 2016, Pages

  Alves Filho, Jose C ^a   Pålsson McDermott, Eva M ^b  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Cancer; Glycolysis and oxidative phosphorylation; HIF 1 ; Immunometabolism; Inflammation; PKM2

Indexed keywords

HYPOXIA INDUCIBLE FACTOR 1ALPHA; LACTATE DEHYDROGENASE; PYRUVATE KINASE;

CANCER GROWTH; CELL CYCLE ASSAY; CONFORMATIONAL TRANSITION; CYTOSKELETON; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; GENE EXPRESSION; GENE SILENCING; GLYCOLYSIS; INFLAMMATION; NONHUMAN; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; REVIEW; SIGNAL TRANSDUCTION;

EID: 84966908058     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00145     Document Type: Review

References (69)

1. Warburg O. Metabolism of tumours. Biochem Z (1923) 142:317-33
2. Palsson-McDermott EM, O'Neill LA. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays (2013) 35(11):965-73. doi: 10.1002/bies.201300084
3. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell (2015) 162(6):1229-41. doi:10.1016/j.cell.2015.08.016
4. Israelsen WJ, Vander Heiden MG. Pyruvate kinase: function, regulation and role in cancer. Semin Cell Dev Biol (2015) 43:43-51. doi:10.1016/j.semcdb.2015.08.004
5. Yang W, Lu Z. Pyruvate kinase M2 at a glance. J Cell Sci (2015) 128(9):1655-60. doi:10.1242/jcs.174870
6. Imamura K, Tanaka T. Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies. J Biochem (1972) 71(6):1043-51
7. Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A (2010) 107(5):1894-9. doi:10.1073/pnas.0914845107
8. Eigenbrodt E, Leib S, Kramer W, Friis RR, Schoner W. Structural and kinetic differences between the M2 type pyruvate kinases from lung and various tumors. Biomed Biochim Acta (1983) 42(11-12):S278-82
9. Takenaka M, Noguchi T, Sadahiro S, Hirai H, Yamada K, Matsuda T, et al. Isolation and characterization of the human pyruvate kinase M gene. Eur J Biochem (1991) 198(1):101-6. doi:10.1111/j.1432-1033.1991.tb15991.x
10. Takenaka M, Yamada K, Lu T, Kang R, Tanaka T, Noguchi T. Alternative splicing of the pyruvate kinase M gene in a minigene system. Eur J Biochem (1996) 235(1-2):366-71. doi:10.1111/j.1432-1033.1996.00366.x
11. Noguchi T, Inoue H, 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 (1986) 261(29):13807-12
12. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature (2010) 463(7279):364-8. doi:10.1038/nature08697
13. Wang Z, Chatterjee D, Jeon HY, Akerman M, Vander Heiden MG, Cantley LC, et al. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J Mol Cell Biol (2012) 4(2):79-87. doi:10.1093/jmcb/mjr030
14. Bluemlein K, Grüning NM, Feichtinger RG, Lehrach H, Kofler B, Ralser M. No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis. Oncotarget (2011) 2(5):393-400. doi:10.18632/oncotarget.278
15. Zhan C, Yan L, Wang L, Ma J, Jiang W, Zhang Y, et al. Isoform switch of pyruvate kinase M1 indeed occurs but not to pyruvate kinase M2 in human tumorigenesis. PLoS One (2015) 10(3):e0118663. doi:10.1371/journal.pone.0118663
16. Lu W, Zhang Y, Zhou L, Wang X, Mu J, Jiang L, et al. miR-122 inhibits cancer cell malignancy by targeting PKM2 in gallbladder carcinoma. Tumour Biol (2015). doi:10.1007/s13277-015-4308-z
17. Tang R, Yang C, Ma X, Wang Y, Luo D, Huang C, et al. MiR-let-7a inhibits cell proliferation, migration, and invasion by down-regulating PKM2 in gastric cancer. Oncotarget (2016) 7(5):5972-84. doi:10.18632/oncotarget.6821
18. Wong TS, Liu XB, Chung-Wai Ho A, Po-Wing Yuen A, Wai-Man Ng R, Ignace Wei W. Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer (2008) 123(2):251-7. doi:10.1002/ijc.23583
19. Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol (2010) 12(11):1102-12. doi:10.1093/neuonc/noq080
20. Cottam GL, Hollenberg PF, Coon MJ. Subunit structure of rabbit muscle pyruvate kinase. J Biol Chem (1969) 244(6):1481-6
21. Jurica MS, Mesecar A, Heath PJ, Shi W, Nowak T, Stoddard BL. The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure (1998) 6(2):195-210. doi:10.1016/S0969-2126(98)00021-5
22. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol (2012) 8(10):839-47. doi:10.1038/nchembio1212-1008b
23. Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, et al. Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab (2015) 21(1):65-80. doi:10.1016/j.cmet.2014.12.005
24. Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EE, et al. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol (2010) 79(8):1118-24. doi:10.1016/j.bcp.2009.12.003
25. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G, et al. Serine and glycine metabolism in cancer. Trends Biochem Sci (2014) 39(4):191-8. doi:10.1016/j.tibs.2014.02.004
26. Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A, et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature (2012) 491(7424):458-62. doi:10.1038/nature11540
27. Keller KE, Tan IS, Lee YS. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science (2012) 338(6110):1069-72. doi:10.1126/science.1224409
28. Mor I, Carlessi R, Ast T, Feinstein E, Kimchi A. Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase. Oncogene (2012) 31(6):683-93. doi:10.1038/onc.2011.264
29. Vijayvargiya R, Schwark WS, Singhal RL. Pyruvate kinase: modulation by L-phenylalanine and L-alanine. Can J Biochem (1969) 47(9):895-8. doi:10.1139/o69-140
30. Weber G. Inhibition of human brain pyruvate kinase and hexokinase by phenylalanine and phenylpyruvate: possible relevance to phenylketonuric brain damage. Proc Natl Acad Sci U S A (1969) 63(4):1365-9. doi:10.1073/pnas.63.4.1365
31. Ashizawa K, McPhie P, Lin KH, Cheng SY. An in vitro novel mechanism of regulating the activity of pyruvate kinase M2 by thyroid hormone and fructose 1, 6-bisphosphate. Biochemistry (1991) 30(29):7105-11. doi:10.1021/bi00243a010
32. Morgan HP, O'Reilly FJ, Wear MA, O'Neill JR, Fothergill-Gilmore LA, Hupp T, et al. M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation. Proc Natl Acad Sci U S A (2013) 110(15):5881-6. doi:10.1073/pnas.1217157110
33. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal (2009) 2(97):ra73. doi:10.1126/scisignal.2000431
34. McDonnell SR, Hwang SR, Rolland D, Murga-Zamalloa C, Basrur V, Conlon KP, et al. Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma. Blood (2013) 122(6):958-68. doi:10.1182/blood-2013-01-482026
35. Iansante V, Choy PM, Fung SW, Liu Y, Chai JG, Dyson J, et al. PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nat Commun (2015) 6:7882. doi:10.1038/ncomms8882
36. Chaiyawat P, Chokchaichamnankit D, Lirdprapamongkol K, Srisomsap C, Svasti J, Champattanachai V. Alteration of O-GlcNAcylation affects serine phosphorylation and regulates gene expression and activity of pyruvate kinase M2 in colorectal cancer cells. Oncol Rep (2015) 34(4):1933-42. doi:10.3892/or.2015.4178
37. Kung C, Hixon J, Choe S, Marks K, Gross S, Murphy E, et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem Biol (2012) 19(9):1187-98. doi:10.1016/j.chembiol.2012.07.021
38. Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene (2011) 30(42):4297-306. doi:10.1038/onc.2011.137
39. Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science (2011) 334(6060):1278-83. doi:10.1126/science.1211485
40. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol (2012) 14(12):1295-304. doi:10.1038/ncb2629
41. Yang W, Lu Z. Nuclear PKM2 regulates the Warburg effect. Cell Cycle (2013) 12(19):3154-8. doi:10.4161/cc.26182
42. Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell (2013) 52(3):340-52. doi:10.1016/j.molcel.2013.09.004
43. Spoden GA, Morandell D, Ehehalt D, Fiedler M, Jansen-Dürr P, Hermann M, et al. The SUMO-E3 ligase PIAS3 targets pyruvate kinase M2. J Cell Biochem (2009) 107(2):293-302. doi:10.1002/jcb.22125
44. Bhardwaj A, Das S. SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions. Proc Natl Acad Sci U S A (2016) 113(5):E538-47. doi:10.1073/pnas.1520045113
45. Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1alpha-mediated glucose metabolism. Proc Natl Acad Sci U S A (2014) 111(1):279-84. doi:10.1073/pnas.1311249111
46. Steták A, Veress R, Ovádi J, Csermely P, Kéri G, Ullrich A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res (2007) 67(4):1602-8. doi:10.1158/0008-5472.CAN-06-2870
47. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell (2011) 145(5):732-44. doi:10.1016/j.cell.2011.03.054
48. Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget (2011) 2(7):551-6. doi:10.18632/oncotarget.299
49. Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol (2008) 40(5):1043-54. doi:10.1016/j.biocel.2007.11.009
50. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature (2011) 480(7375):118-22. doi:10.1038/nature10598
51. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell (2012) 150(4):685-96. doi:10.1016/j.cell.2012.07.018
52. Jiang Y, Li X, Yang W, Hawke DH, Zheng Y, Xia Y, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell (2014) 53(1):75-87. doi:10.1016/j.molcel.2013.11.001
53. Gao X, Wang H, Yang JJ, Liu X, Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell (2012) 45(5):598-609. doi:10.1016/j.molcel.2012.01.001
54. Hosios AM, Fiske BP, Gui DY, Vander Heiden MG. Lack of evidence for PKM2 protein kinase activity. Mol Cell (2015) 59(5):850-7. doi:10.1016/j.molcel.2015.07.013
55. Kotas ME, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell (2015) 160(5):816-27. doi:10.1016/j.cell.2015.02.010
56. Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab (2012) 23(11):560-6. doi:10.1016/j.tem.2012.06.010
57. Iqbal MA, Gupta V, Gopinath P, Mazurek S, Bamezai RN. Pyruvate kinase M2 and cancer: an updated assessment. FEBS Lett (2014) 588(16):2685-92. doi:10.1016/j.febslet.2014.04.011
58. Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, et al. PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun (2014) 5:4436. doi:10.1038/ncomms5436
59. Shirai T, Nazarewicz RR, Wallis BB, Yanes RE, Watanabe R, Hilhorst M, et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med (2016) 213(3):337-54. doi:10.1084/jem.20150900
60. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med (2000) 192(4):565-70. doi:10.1084/jem.192.4.565
61. Yang P, Li Z, Li H, Lu Y, Wu H, Li Z. Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer. Cell Signal (2015) 27(7):1525-32. doi:10.1016/j.cellsig.2015.02.032
62. Tang Q, Ji Q, Xia W, Li L, Bai J, Ni R, et al. Pyruvate kinase M2 regulates apoptosis of intestinal epithelial cells in Crohn's disease. Dig Dis Sci (2015) 60(2):393-404. doi:10.1007/s10620-014-3189-0
63. Chung-Faye G, Hayee B, Maestranzi S, Donaldson N, Forgacs I, Sherwood R. Fecal M2-pyruvate kinase (M2-PK): a novel marker of intestinal inflammation. Inflamm Bowel Dis (2007) 13(11):1374-8. doi:10.1002/ibd.20214
64. Day AS, Judd T, Lemberg DA, Leach ST. Fecal M2-PK in children with Crohn's disease: a preliminary report. Dig Dis Sci (2012) 57(8):2166-70. doi:10.1007/s10620-012-2215-3
65. Bertrand J, Marion-Letellier R, Azhar S, Chan P, Legrand R, Goichon A, et al. Glutamine enema regulates colonic ubiquitinated proteins but not proteasome activities during TNBS-induced colitis leading to increased mitochondrial activity. Proteomics (2015) 15(13):2198-210. doi:10.1002/pmic.201400304
66. Li XJ, Xu M, Zhao XQ, Zhao JN, Chen FF, Yu W, et al. Proteomic analysis of synovial fibroblast-like synoviocytes from rheumatoid arthritis. Clin Exp Rheumatol (2013) 31(4):552-8
67. Goldberg MS, Sharp PA. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med (2012) 209(2):217-24. doi:10.1084/jem.20111487
68. Qin X, Du Y, Chen X, Li W, Zhang J, Yang J. Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown. Cell Biosci (2014) 4:20. doi:10.1186/2045-3701-4-20
69. Morfouace M, Lalier L, Oliver L, Cheray M, Pecqueur C, Cartron PF, et al. Control of glioma cell death and differentiation by PKM2-Oct4 interaction. Cell Death Dis (2014) 5:e1036. doi:10.1038/cddis.2013.561