Pyruvate kinase M2 and lactate dehydrogenase a are overexpressed in pancreatic cancer and correlate with poor outcome

PLoS ONE

Volumn 11, Issue 3, 2016, Pages

  Mohammad, Goran Hamid ^a,b   Damink, S W M Olde ^a,c   Malago, Massimo ^a   Dhar, Dipok Kumar ^a,d   Pereira, Stephen P ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF SULAIMANI   (Iraq)

^c MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

^d KING FAISAL SPECIALIST HOSPITAL AND RESEARCH CENTER   (Saudi Arabia)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CD8 ANTIGEN; KI 67 ANTIGEN; LACTATE DEHYDROGENASE; LACTATE DEHYDROGENASE A; PYRUVATE KINASE; PYRUVATE KINASE M2; TUMOR MARKER; UNCLASSIFIED DRUG; ISOENZYME; LACTATE DEHYDROGENASE 5;

ADULT; AGED; ARTICLE; CANCER PATIENT; CANCER PROGNOSIS; CANCER SIZE; CANCER SURVIVAL; CARCINOGENESIS; CD8+ T LYMPHOCYTE; CLINICAL FEATURE; COHORT ANALYSIS; CONTROLLED STUDY; DISEASE ACTIVITY; FEMALE; HISTOPATHOLOGY; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; MAJOR CLINICAL STUDY; MALE; OUTCOME ASSESSMENT; PANCREAS ADENOMA; PANCREAS CANCER; PANCREAS CYST; PANCREATIC CANCER CELL LINE; PROTEIN EXPRESSION; SURVIVAL TIME; BIOSYNTHESIS; EARLY CANCER DIAGNOSIS; ENZYMOLOGY; GENE EXPRESSION; GENE EXPRESSION REGULATION; GLYCOLYSIS; LYMPHOCYTE COUNT; METABOLISM; MIDDLE AGED; MORTALITY; PANCREAS; PANCREAS CARCINOMA; PANCREAS TUMOR; PATHOLOGY; PHYSIOLOGY; PROCEDURES; PROGNOSIS; SURVIVAL RATE; TUMOR CELL LINE; VERY ELDERLY;

ADULT; AGED; AGED, 80 AND OVER; BIOMARKERS, TUMOR; CARCINOMA, PANCREATIC DUCTAL; CD8-POSITIVE T-LYMPHOCYTES; CELL LINE, TUMOR; EARLY DETECTION OF CANCER; FEMALE; GENE EXPRESSION; GENE EXPRESSION REGULATION, NEOPLASTIC; GLYCOLYSIS; HUMANS; IMMUNOHISTOCHEMISTRY; ISOENZYMES; KI-67 ANTIGEN; L-LACTATE DEHYDROGENASE; LYMPHOCYTE COUNT; MALE; MIDDLE AGED; PANCREAS; PANCREATIC NEOPLASMS; PROGNOSIS; PYRUVATE KINASE; SURVIVAL RATE;

EID: 84962176550     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0151635     Document Type: Article

References (66)

1. American Cancer Society. Cancer Fact and Figures 2014. Accessed 16 Dec 2014. Available: http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2014. 2014.
2. Cancer Research UK. Pancreatic Cancer Statistics. Accessed 20 Feb 2015. Available: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/pancreas/. 2014.
3. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364(19): 1817-25. doi: 10.1056/NEJMoa1011923 PMID: 21561347
4. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: Results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013; 31(1): 23-9. doi: 10.1200/JCO.2012.44.4869 PMID: 23213101
5. Wong N, Ojo D, Yan J, Tang D. PKM2 contributes to cancer metabolism. Cancer Letters. 2015; 656 (2): 184-191.
6. Iqbal MA, Gupta V, Gopinath P, Mazurek S, Bamezai RNK Pyruvate kinase M2 and cancer: an updated assessment. FEBS Lett. Federation of European Biochemical Societies; 2014; 588 (16): 2685-92. doi: 10.1016/j.febslet.2014.04.011 PMID: 24747424
7. Wang H-J, Hsieh Y-J, Cheng W-C, Lin C-P, Lin Y, Yang S-F, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1a-mediated glucose metabolism. Proc Natl Acad Sci U SA. 2014; 111(1): 279-84. doi: 10.1073/pnas.1311249111 PMID: 24344305
8. Warner S, Carpenter K, Bearss D. Activators of PKM2 in cancer metabolism. Future Med Chem. 2014; 06: 1167-78.
9. Gao Xueliang, Wang Haizhen, Jenny J. Yang, Liu Xiaowei and Z-RL. Pyruvate Kinase M2 Regulates Gene Transcription by Acting as A Protein Kinas. 2012; 45(5): 598-609.
10. Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 2011; 43(7): 969-80. doi: 10.1016/j.biocel.2010.02.005 PMID: 20156581
11. Kumar Y, Mazurek S, Yang S, Failing K, Winslet M, Fuller B, et al. In vivo factors influencing tumour M2-pyruvate kinase level in human pancreatic cancer cell lines. Tumour Biol. 2010; 31(2): 69-77. doi: 10.1007/s13277-009-0010-3 PMID: 20358419
12. 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. Elsevier Inc.; 2010; 79 (8): 1118-24. doi: 10.1016/j.bcp.2009.12.003 PMID: 20005212
13. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452 (7184): 230-3. doi: 10.1038/nature06734 PMID: 18337823
14. Jurica MS, Mesecara, Heath PJ, Shi W, Nowak T, Stoddard BL. The allosteric regulation of pyruvate kinase byfructose-1,6-bisphosphate. Structure. 1998; 6(2): 195-210. PMID: 9519410
15. Kumar Y, Tapuria N, Kirmani N, Davidson BR. Tumour M2-pyruvate kinase: a gastrointestinal cancer marker. Eur J Gastroenterol Hepatol. 2007; 19(3): 265-76. PMID: 17301655
16. Li YG, Zhang N. Clinical significance of serum tumour M2-PK and CA19-9 detection in the diagnosis of cholangiocarcinoma. Dig Liver Dis. 2009; 41(8): 605-8. doi: 10.1016/j.dld.2008.11.010 PMID: 19168405
17. Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005; 15(4): 300-8. PMID: 15908230
18. Hardt P. D., and Ewald N. Tumor M2 pyruvate kinase: a tumor marker and its clinical application in gastrointestinal malignancy. Expert Rev Mol Diagn. 2008; 8: 579-85. doi: 10.1586/14737159.8.5.579 PMID: 18785806
19. Spoden G a, Rostek U, Lechner S, Mitterberger M, Mazurek S, 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. Elsevier Inc.; 2009; 315(16): 2765-74. doi: 10.1016/j.yexcr.2009.06.024 PMID: 19563799
20. Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase a in cancer: A promising target for diagnosis and therapy. IUBMB Life. 2013. p. 904-10. doi: 10.1002/iub.1216 PMID: 24265197
21. Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013; 123(9): 3685-92. doi: 10.1172/JCI69741 PMID: 23999443
22. Fiume L, Vettraino M, Stefano G Di. Inhibition of lactate dehydrogenase activity as an approach to cancertherapy. 2014; 429-45. doi: 10.4155/fmc.13.206 PMID: 24635523
23. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA. 2010; 107 (5): 2037-42. doi: 10.1073/pnas.0914433107 PMID: 20133848
24. Billiard J, Dennison JB, Briand J, Annan RS, Chai D, Colón M, et al. Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells. Cancer Metab. 2013; 1(1): 19. doi: 10.1186/2049-3002-1-19 PMID: 24280423
25. Yu Y, Deck JA, Hunsaker LA, Deck LM, Royer RE, Goldberg E, et al. Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4. Biochem Pharmacol. 2001; 62(1): 81-9. PMID: 11377399
26. Xue J-J, Chen Q-Y, Kong M-Y, Zhu C-Y, Gen Z-R, Wang Z-L. Synthesis, cytotoxicity for mimics of catalase: Inhibitors of lactate dehydrogenase and hypoxia inducible factor. Eur J Med Chem. Elsevier; 2014; 80: 1-7. doi: 10.1016/j.ejmech.2014.04.035 PMID: 24763359
27. Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, et al. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. Nature Publishing Group; 2003; 89 (5): 877-85. PMID: 12942121
28. Le A, Rajeshkumar N V, Maitra A, Dang CV. Conceptual framework for cutting the pancreatic cancer fuel supply. Clin Cancer Res. 2012; 18(16): 4285-90. doi: 10.1158/1078-0432.CCR-12-0041 PMID: 22896695
29. Zhao D, Xiong Y, Lei Q-Y, Guan K-L. LDH-A Acetylation: implication in Pancreatic Cancer Initiation and Diagnosis. Oncotarget. 2013; 4(6): 802-803. PMID: 23868819
30. Yu Y, Liao M, Liu R, Chen J, Feng H, Fu Z. Overexpression of lactate dehydrogenase-A in human intrahepatic cholangiocarcinoma: its implication for treatment. World J Surg Oncol. 2014; 12: 78. doi: 10.1186/1477-7819-12-78 PMID: 24679073
31. Zhou C, Li X, Sun H, Zhang B, Han Y, Jiang Y, et al. Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells. IUBMB Life. Wiley Online Library; 2012; 64(9): 775-82. doi: 10.1002/iub.1066 PMID: 22807066
32. Rong Y, Wu W, Ni X, Kuang T, Jin D, Wang D, et al. Lactate dehydrogenase A is overexpressed in pancreatic cancer and promotes the growth of pancreatic cancer cells. Tumour Biol. 2013; 34(3): 1523-30. doi: 10.1007/s13277-013-0679-1 PMID: 23404405
33. Anastasiou D, Yu Y, Israelsen WJ, Jiang J, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012 Oct; 8(10): 839-47. PMID: 22922757
34. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, et al. CD8+tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. LWW; 2004; 28(1): e26-31. PMID: 14707745
35. Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. Predominant infiltration of macrophages and CD8+T cells in cancer nests is a significant predictor of survival in stage IVnonsmall cell lung cancer. Cancer. Wiley Online Library; 2008; 113(6): 1387-95. doi: 10.1002/cncr.23712 PMID: 18671239
36. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. National Acad Sciences; 2005; 102(51): 18538-43. PMID: 16344461
37. Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. American Society of Clinical Oncology; 2009; 27(35): 5944-51. doi: 10.1200/JCO.2008.19.6147 PMID: 19858404
38. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, et al. Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma clinicopathologic demonstration of antitumor immunity. Cancer Res. AACR; 2001; 61(13): 5132-6. PMID: 11431351
39. Ashida A, Boku N, Aoyagi K, Sato H, Tsubosa Y, Minashi K, et al. Expression profiling of esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy: clinical implications. Int J Oncol. Spandidos Publications; 2006; 28(6): 1345-52. PMID: 16685435
40. Ikeguchi M, Oi K, Hirooka Y, Kaibara N. CD8+ lymphocyte infiltration and apoptosis in hepatocellular carcinoma. Eur J Surg Oncol. 2004; 30(1): 53-7. PMID: 14736523
41. Mahmoud SM a, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011; 29(15): 1949-55. doi: 10.1200/JCO.2010.30.5037 PMID: 21483002
42. Li Z, Yang P, Li Z. The multifaceted regulation and functions of PKM2 in tumor progression. Biochim Biophys Acta. Elsevier B.V.; 2014; 1864(2): 285-296.
43. Dhar DK, Olde Damink SWM, Brindley JH, Godfrey A, Chapman MH, Sandanayake NS, et al. Pyruvate kinase M2 is a novel diagnostic marker and predicts tumour progression in human biliary tract cancer. Cancer. 2013 Feb; 119(3): 575-85. doi: 10.1002/cncr.27611 PMID: 22864959
44. Wong N, De Melo J, Tang D. PKM2, a central point of regulation in cancer metabolism. Int J Cell Biol. 2013;(2013): 1-11.
45. Singh S, Tan M, Rameshwar P. Cancer Metabolism: Targeting metabolic pathways in cancer therapy. Cancer Lett. 2015; 356: 147-8. doi: 10.1016/j.canlet.2014.06.002 PMID: 24956174
46. Kumar Y, Gurusamy K, Pamecha V, Davidson BR. Tumor M2-pyruvate kinase as tumor marker in exocrine pancreatic cancer a meta-analysis. Pancreas. 2007; 35(2): 114-9. PMID: 17632316
47. Goonetilleke KS, Mason JM, Siriwardana P, King NK, France MW, Siriwardena AK. Diagnostic and prognostic value of plasma tumor M2 pyruvate kinase in periampullary cancer: evidence for a novel biological marker of adverse prognosis. Pancreas. 2007; 34(3): 318-24. PMID: 17414054
48. Joergensen MT, Heegaard NHH, Schaffalitzky de Muckadell OB. Comparison of plasma Tu-M2-PK and CA19-9 in pancreatic cancer. Pancreas. 2010; 39(2): 243-7. doi: 10.1097/MPA.0b013e3181bae8ab PMID: 19820423
49. Shi M, Cui J, Du J, Wei D, Jia Z, Zhang J, et al. A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. Clin Cancer Res. AACR; 2014; 20(16): 4370-80. doi: 10.1158/1078-0432.CCR-14-0186 PMID: 24947925
50. He T-L, Zhang Y-J, Jiang H, Li X, Zhu H, Zheng K-L. The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer. Med Oncol. Springer; 2015; 32(7): 1-8.
51. Kachel P, Trojanowicz B, Sekulla C, Prenzel H, Dralle H, Hoang-Vu C. Phosphorylation of pyruvate kinase M2 and lactate dehydrogenase A by fibroblast growth factor receptor 1 in benign and malignant thyroid tissue. BMC Cancer. Bio Med Central Ltd; 2015; 15(1): 140.
52. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependentphosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. Nature Publishing Group; 2012; 14 (12): 1295-304. doi: 10.1038/ncb2629 PMID: 23178880
53. Hitosugi T, Kang S, Vander Heiden MG, Chung T-W, Elf S, Lythgoe K, et al. Tyrosine phosphorylation inhibits PKM2to promote the Warburg effect and tumor growth. Sci Signal. NIH Public Access; 2009; 2 (97): ra73. doi: 10.1126/scisignal.2000431 PMID: 19920251
54. Sun X, Sun Z, Zhu Z, Li C, Zhang J, Xu H, et al. Expression of SIP1 is strongly correlated with LDHA and shows a significantly poor outcome in gastric cancer. Tumor Biol. Springer; 2015; 1-10.
55. Wang Y, Zhang X, Zhang Y, Zhu Y, Yuan C, Qi B, et al. Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma. Cancer Biol Ther. Taylor & Francis; 2015; (just-accepted): 0.
56. Rajeshkumar N V., Dutta P, Yabuuchi S, de Wilde RF, Matrinez GV., Lea, et al. Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Research. 2015. p. 713-745.
57. Feng J, Ma T, Ge Z, Lin J, Ding W, Chen H, et al. PKM2gene regulates the behavior of pancreatic cancer cells via mitogen-activated protein kinase pathways. Mol Med Rep. Spandidos Publications; 2015; 11(3): 2111-7. doi: 10.3892/mmr.2014.2990 PMID: 25411978
58. Azoitei N, Rehbein G, Genze F, Brobovich S, Armacki M, Fiedler K, et al. Role of Pyruvate kinase M2 (PKM2) in tumor growth, cancer cell migration and tumor angiogenesis. Z Gastroenterol. 51(08): K55.
59. 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 PMID: 24316223
60. Parra-Bonilla G, Alvarez DF, Alexeyev M, Vasauskas A, Stevens T. Lactate Dehydrogenase A Expression Is Necessary to Sustain Rapid Angiogenesis of Pulmonary Microvascular Endothelium. PLoS One. 2013; 8(9).
61. Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L, et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci. 2014; 111(35): 12823-12828. doi: 10.1073/pnas.1413933111 PMID: 25136121
62. Liu W-R, Tian M-X, Yang L-X, Lin Y-L, Jin L, Ding Z-B, et al. PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma. Oncotarget. Impact Journals, LLC; 2015; 6(2): 846. PMID: 25514599
63. Lockney NA, Zhang M, Lu Y, Sopha SC, Washington MK, Merchant N, et al. Pyruvate Kinase Muscle Isoenzyme 2 (PKM2) Expression Is Associated with Overall Survival in Pancreatic Ductal Adenocarcinoma. J Gastrointest Cancer. 2015; 46 (4): 390-398. doi: 10.1007/s12029-015-9764-6 PMID: 26385349
64. Lim JY, Yoon SO, Seol SY, Hong SW, Kim JW, Choi SH, et al. Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer. World J Gastroenterol. 2012; 18: 4037-43. doi: 10.3748/wjg.v18.i30.4037 PMID: 22912555
65. Zhang X, He C, He C, Chen B, Liu Y, Kong M, et al. Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract. 2013; 209: 510-5. doi: 10.1016/j.prp.2013.06.005 PMID: 23880164
66. Li J, Yang Z, Zou Q, Yuan Y, Liang L, Zeng G, et al. PKM2 and ACVR 1Care prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol. 2014; 16: 200-7. doi: 10.1007/s12094-013-1063-8 PMID: 23793810