Phosphorylation of pyruvate kinase M2 and lactate dehydrogenase A by fibroblast growth factor receptor 1 in benign and malignant thyroid tissue

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• 作者：Paul Kachel (1)
  Bogusz Trojanowicz (2)
  Carsten Sekulla (1)
  Hanna Prenzel (1)
  Henning Dralle (1)
  Cuong Hoang-Vu (1)
  
  1. Department of General ; Visceral and Vascular Surgery ; Faculty of Medicine ; Martin-Luther-University of Halle-Wittenberg ; Halle/Saale ; Germany
  2. Department of Internal Medicine II ; Faculty of Medicine ; Martin-Luther-University of Halle-Wittenberg ; Halle/Saale ; Germany
  
• 关键词：Pyruvate Kinase M2 ; Lactate dehydrogenase A ; Fibroblast growth factor receptor 1 ; Warburg effect ; Thyroid ; Tumour marker
• 刊名：BMC Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：15
• 期：1
• 全文大小：2,211 KB
• 参考文献：1. Warburg, O (1924) 眉ber den Stoffwechsel der Carcinomzelle. Naturwissenschaften 12: pp. 1131-7 CrossRef
  2. Warburg, O (1956) On the origin of cancer cells. Science 123: pp. 309-14 CrossRef
  3. Prigione, A, Fauler, B, Lurz, R, Lehrach, H, Adjaye, J (2010) The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 28: pp. 721-33 CrossRef
  4. Colombo, SL, Palacios-Callender, M, Frakich, N, Leon, J, Schmitt, CA, Boorn, L (2010) Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes. Proc Natl Acad Sci U S A 107: pp. 18868-73 CrossRef
  5. Noguchi, T, Inoue, H, Tanaka, T (1986) The M1-and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem 261: pp. 13807-12
  6. Bluemlein, KK, Gr眉ning, N-MN, Feichtinger, RGR, Lehrach, HH, Kofler, BB, Ralser, MM (2011) No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis. Oncotarget 2: pp. 393-400
  7. Christofk, HR, Vander Heiden, MG, Harris, MH, Ramanathan, A, Gerszten, RE, Wei, R (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: pp. 230-3 CrossRef
  8. Mazurek S. Pyruvate kinase type M2, a key regulator within the tumour metabolome and a tool for metabolic profiling of tumours. Ernst Schering Found Symp Proc. 2007;99鈥?24.
  9. Christofk, HRH, Vander Heiden, MGM, Wu, NN, Asara, JMJ, Cantley, LCL (2008) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452: pp. 181-6 CrossRef
  10. Mazurek, S, Zwerschke, W, Jansen-D眉rr, P, Eigenbrodt, E (2001) Effects of the human papilloma virus HPV-16 E7 oncoprotein on glycolysis and glutaminolysis: role of pyruvate kinase type M2 and the glycolytic-enzyme complex. Biochem J 356: pp. 247-56 CrossRef
  11. Gr眉ning, N-M, Rinnerthaler, M, Bluemlein, K, M眉lleder, M, Wamelink, MMC, Lehrach, H (2011) Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell Metab 14: pp. 415-27 CrossRef
  12. Hitosugi, T, Kang, S, Vander Heiden, MG, Chung, TW, Elf, S, Lythgoe, K (2009) Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth. Sci Signal 2: pp. ra73 CrossRef
  13. Gao, X, Wang, H, Yang, JJ, Liu, X, Liu, Z-R (2012) Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell 45: pp. 598-609 CrossRef
  14. Luo, W, Hu, H, Chang, R, Zhong, J, Knabel, M, O鈥橫eally, R (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145: pp. 732-44 CrossRef
  15. Luo, W, Semenza, GL (2011) Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2: pp. 551-6
  16. Lv, L, Xu, Y-P, Zhao, D, Li, F-L, Wang, W, Sasaki, N (2013) Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell 52: pp. 340-52 CrossRef
  17. Luo, W, Semenza, GL (2012) Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab 23: pp. 560-6 CrossRef
  18. Hathurusinghe, HR, Goonetilleke, KS, Siriwardena, AK (2007) Current Status of Tumor M2 Pyruvate Kinase (Tumor M2-PK) as a Biomarker of Gastrointestinal Malignancy. Ann Surg Oncol 14: pp. 2714-20 CrossRef
  19. Dhar, DK, Olde Damink, SWM, Brindley, JH, Godfrey, A, Chapman, MH, Sandanayake, NS (2012) Pyruvate kinase M2 is a novel diagnostic marker and predicts tumor progression in human biliary tract cancer. Cancer 119: pp. 575-85 CrossRef
  20. Koukourakis, MI, Giatromanolaki, A, Sivridis, E (2003) Lactate dehydrogenase isoenzymes 1 and 5: differential expression by neoplastic and stromal cells in non-small cell lung cancer and other epithelial malignant tumors. Tumour Biol 24: pp. 199-202 CrossRef
  21. Hilf, R, Rector, WD, Orlando, RA (1976) Multiple molecular forms of lactate dehydrogenase and glucose 6-phosphate dehydrogenase in normal and abnormal human breast tissues. Cancer 37: pp. 1825-30 CrossRef
  22. Fantin, VR, St-Pierre, J, Leder, P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9: pp. 425-34 CrossRef
  23. Le, A, Cooper, CR, Gouw, AM, Dinavahi, R, Maitra, A, Deck, LM (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci 107: pp. 2037-42 CrossRef
  24. Mirebeau-Prunier, D, Pennec, S, Jacques, C, Fontaine, J-F, Gueguen, N, Boutet-Bouzamondo, N (2013) Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS One 8: pp. e58683 CrossRef
  25. Fan, J, Hitosugi, T, Chung, TW, Xie, J, Ge, Q, Gu, TL (2011) Tyrosine phosphorylation of lactate dehydrogenase a is important for NADH/NAD+ redox homeostasis in cancer cells. Mol Cell Biol 31: pp. 4938-50 CrossRef
  26. Martino, E, Tomlinson, DC, Knowles, MA (2012) A decade of FGF receptor research in bladder cancer: past, present, and future challenges. Ther Adv Urol 2012: pp. 1-10 CrossRef
  27. Reis-Filho, JS, Simpson, PT, Turner, NC, Lambros, MB, Jones, C, Mackay, A (2006) FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res 12: pp. 6652-62 CrossRef
  28. Eswarakumar, VP, Lax, I, Schlessinger, J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16: pp. 139-49 CrossRef
  29. St Bernard, R (2004) Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology 146: pp. 1145-53 CrossRef
  30. Thompson, SD, Franklyn, JA, Watkinson, JC, Verhaeg, JM, Sheppard, MC, Eggo, MC (1998) Fibroblast growth factors 1 and 2 and fibroblast growth factor receptor 1 are elevated in thyroid hyperplasia. J Clin Endocrinol Metab 83: pp. 1336-41 CrossRef
  31. Shim, H, Dolde, C, Lewis, BC, Wu, CS, Dang, G, Jungmann, RA (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A 94: pp. 6658-63 CrossRef
  32. David, CJ, Chen, M, Assanah, M, Canoll, P, Manley, JL (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463: pp. 364-8 CrossRef
  33. Semenza, GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33: pp. 207-14 CrossRef
  34. Chen, M, Zhang, J, Manley, JL (2010) Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA. Cancer Res 70: pp. 8977-80 CrossRef
  35. Burrows, N, Resch, J, Cowen, RL, Wasielewski von, R, Hoang-Vu, C, West, CM (2010) Expression of hypoxia-inducible factor 1 in thyroid carcinomas. Endocr Relat Cancer 17: pp. 61-72 CrossRef
  36. Terrier, P, Sheng, ZM, Schlumberger, M, Tubiana, M, Caillou, B, Travagli, JP (1988) Structure and expression of c-myc and c-fos proto-oncogenes in thyroid carcinomas. Br J Cancer 57: pp. 43 CrossRef
  37. Israelsen, WJ, Dayton, TL, Davidson, SM, Fiske, BP, Hosios, AM, Bellinger, G (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155: pp. 397-409 CrossRef
  38. Yang, W, Xia, Y, Hawke, D, Li, X, Liang, J, Xing, D (2012) PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150: pp. 685-96 CrossRef
  39. Parra-Bonilla, G, Alvarez, DF, Alexeyev, M, Vasauskas, A, Stevens, T (2013) Lactate dehydrogenase a expression is necessary to sustain rapid angiogenesis of pulmonary microvascular endothelium. PLoS One 8: pp. e75984 CrossRef
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

Background Lactate dehydrogenase A (LDHA) and Pyruvate Kinase M2 (PKM2) are important enzymes of glycolysis. Both of them can be phosphorylated and therefore regulated by Fibroblast growth factor receptor 1 (FGFR1). While phosphorylation of LDHA at tyrosine10 leads to tetramerization and activation, phosphorylation of PKM2 at tyrosine105 promotes dimerization and inactivation. Dimeric PKM2 is found in the nucleus and regulates gene transcription. Up-regulation and phosphorylation of LDHA and PKM2 contribute to faster proliferation under hypoxic conditions and promote the Warburg effect. Methods Using western blot and SYBR Green Real time PCR we investigated 77 thyroid tissues including 19 goiter tissues, 11 follicular adenomas, 16 follicular carcinomas, 15 papillary thyroid carcinomas, and 16 undifferentiated thyroid carcinomas for total expression of PKM2, LDHA and FGFR1. Additionally, phosphorylation status of PKM2 and LDHA was analysed. Inhibition of FGFR was performed on FTC133 cells with SU-5402 and Dovitinib. Results All examined thyroid cancer subtypes overexpressed PKM2 as compared to goiter. LDHA was overexpressed in follicular and papillary thyroid cancer as compared to goiter. Elevated phosphorylation of LDHA and PKM2 was detectable in all analysed cancer subtypes. The highest relative phosphorylation levels of PKM2 and LDHA compared to overall expression were found in undifferentiated thyroid cancer. Inhibition of FGFR led to significantly decreased phosphorylation levels of PKM2 and LDHA. Conclusions Our data shows that overexpression and increased phosphorylation of PKM2 and LHDA is a common finding in thyroid malignancies. Phospho-PKM2 and Phospho-LDHA could be valuable tumour markers for thyroglobulin negative thyroid cancer.