Pyruvate dehydrogenase kinases: Therapeutic targets for diabetes and cancers

Diabetes and Metabolism Journal

Volumn 39, Issue 3, 2015, Pages 188-197

  Jeoung, Nam Ho ^a  

^a Catholic University of Daegu   (South Korea)

Author keywords

Diabetes mellitus, type 2; Glucose metabolism; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase; Pyruvate dehydrogenase kinase inhibitor; Warberg effect

Indexed keywords

AZD 7545; DICHLOROACETIC ACID; M 77976; N PHENYL DICHLOROACETAMIDE; NOV 3R; PFZ 3; PROTEIN SERINE THREONINE KINASE INHIBITOR; PYRUVATE DEHYDROGENASE COMPLEX; PYRUVATE DEHYDROGENASE KINASE; PYRUVATE DEHYDROGENASE KINASE 1; PYRUVATE DEHYDROGENASE KINASE 2; PYRUVATE DEHYDROGENASE KINASE 3; PYRUVATE DEHYDROGENASE KINASE 4; RADICICOL; TRIFLUORO 2 HYDROXY 2 METHYLPROPIONIC ACID; UNCLASSIFIED DRUG;

ALLOSTERISM; AMINO TERMINAL SEQUENCE; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; DRUG BINDING SITE; DRUG RECEPTOR BINDING; ENZYME ACTIVITY; ENZYME INHIBITION; GLUCOSE METABOLISM; HUMAN; IC50; INSULIN RESISTANCE; LACTIC ACIDOSIS; LIPOAMIDE BINDING DOMAIN; LIVER CIRRHOSIS; METABOLIC DISORDER; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATHOGENESIS; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW;

EID: 84932618651     PISSN: 22336079     EISSN: 22336087     Source Type: Journal    
DOI: 10.4093/dmj.2015.39.3.188     Document Type: Review

References (65)

1. Rahimi Y, Camporez JP, Petersen MC, Pesta D, Perry RJ, Jurczak MJ, Cline GW, Shulman GI. Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance. Proc Natl Acad Sci USA 2014; 111:16508-13.
2. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785-9.
3. Garland PB, Newsholme EA, Randle PJ. Regulation of glucose uptake by muscle. 9. Effects of fatty acids and ketone bodies, and of alloxan-diabetes and starvation, on pyruvate metabolism and on lactate-pyruvate and L-glycerol 3-phosphate-dihydroxyacetone phosphate concentration ratios in rat heart and rat diaphragm muscles. Biochem J 1964;93:665-78.
4. Jeoung NH, Harris RA. Role of pyruvate dehydrogenase kinase 4 in regulation of blood glucose levels. Korean Diabetes J 2010; 34:274-83.
5. Sugden MC, Bulmer K, Holness MJ. Fuel-sensing mechanisms integrating lipid and carbohydrate utilization. Biochem Soc Trans 2001;29(Pt 2):272-8.
6. Harris RA, Bowker-Kinley MM, Huang B, Wu P. Regulation of the activity of the pyruvate dehydrogenase complex. Adv Enzyme Regul 2002;42:249-59.
7. Del Prato S, Bonadonna RC, Bonora E, Gulli G, Solini A, Shank M, DeFronzo RA. Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. J Clin Invest 1993;91:484-94.
8. Mondon CE, Jones IR, Azhar S, Hollenbeck CB, Reaven GM. Lactate production and pyruvate dehydrogenase activity in fat and skeletal muscle from diabetic rats. Diabetes 1992;41: 1547-54.
9. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3:177-85.
10. Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 2010;20:51-6.
11. Preiser JC, Moulart D, Vincent JL. Dichloroacetate administration in the treatment of endotoxin shock. Circ Shock 1990; 30:221-8.
12. Sugden MC, Holness MJ. Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem 2006;112:139-49.
13. Rowles J, Scherer SW, Xi T, Majer M, Nickle DC, Rommens JM, Popov KM, Harris RA, Riebow NL, Xia J, Tsui LC, Bogardus C, Prochazka M. Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem 1996;271:22376-82.
14. Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM. Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation. J Biol Chem 1998;273:17680-8.
15. Huang B, Wu P, Popov KM, Harris RA. Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney. Diabetes 2003;52:1371-6.
16. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 1998; 329(Pt 1):191-6.
17. Wu P, Blair PV, Sato J, Jaskiewicz J, Popov KM, Harris RA. Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues. Arch Biochem Biophys 2000;381:1-7.
18. Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J 1998;329(Pt 1): 197-201.
19. Jeong JY, Jeoung NH, Park KG, Lee IK. Transcriptional regulation of pyruvate dehydrogenase kinase. Diabetes Metab J 2012; 36:328-35.
20. Cairns RA, Papandreou I, Sutphin PD, Denko NC. Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci USA 2007;104: 9445-50.
21. Ding G, Huang G, Liu HD, Liang HX, Ni YF, Ding ZH, Ni GY, Hua HW. MiR-199a suppresses the hypoxia-induced proliferation of non-small cell lung cancer cells through targeting HIF1alpha. Mol Cell Biochem 2013;384:173-80.
22. Newington JT, Pitts A, Chien A, Arseneault R, Schubert D, Cumming RC. Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect. PLoS One 2011;6:e19191.
23. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006;3:187-97.
24. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15: 551-78.
25. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000;2:423-7.
26. Semenza GL. Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 2011;76:347-53.
27. Howangyin KY, Silvestre JS. Diabetes mellitus and ischemic diseases: molecular mechanisms of vascular repair dysfunction. Arterioscler Thromb Vasc Biol 2014;34:1126-35.
28. McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 2008;283:22700-8.
29. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 2006;70:1469-80.
30. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 2006;113:2630-41.
31. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007;11:37-51.
32. Harris RA, Huang B, Wu P. Control of pyruvate dehydrogenase kinase gene expression. Adv Enzyme Regul 2001;41:269-88.
33. Jeoung NH, Rahimi Y, Wu P, Lee WN, Harris RA. Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice. Biochem J 2012;443:829-39.
34. Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L, Bolanos JP, Rakovic A, Spin JM, Stubbendorff M, Ikeno F, Langer F, Zeller T, Schulte-Uentrop L, Stoehr A, Itagaki R, Haddad F, Eschenhagen T, Blankenberg S, Kiefmann R, Reichenspurner H, Velden J, Klein C, Yeung A, Robbins RC, Tsao PS, Schrepfer S. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature 2014;509:641-4.
35. Byun JK, Choi YK, Kang YN, Jang BK, Kang KJ, Jeon YH, Lee HW, Jeon JH, Koo SH, Jeong WI, Harris RA, Lee IK, Park KG. Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology 2015;61:953-64.
36. Baker JC, Yan X, Peng T, Kasten S, Roche TE. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. J Biol Chem 2000;275:15773-81.
37. Tuganova A, Boulatnikov I, Popov KM. Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex. Biochem J 2002; 366(Pt 1):129-36.
38. Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 2008; 283:28106-14.
39. Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blumlein K, Wanker EE, Ralser M, Cramer T, Adjaye J. HIF1alpha modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells 2014;32:364-76.
40. Lu CW, Lin SC, Chien CW, Lin SC, Lee CT, Lin BW, Lee JC, Tsai SJ. Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer. Am J Pathol 2011;179:1405-14.
41. Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007;64:830-49.
42. Jeoung NH, Wu P, Joshi MA, Jaskiewicz J, Bock CB, Depaoli-Roach AA, Harris RA. Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. Biochem J 2006;397:417-25.
43. Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab 2008;295:E46-54.
44. Hwang B, Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet. Biochem J 2009;423: 243-52.
45. Liu Z, Chen X, Wang Y, Peng H, Wang Y, Jing Y, Zhang H. PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade. J Biol Chem 2014;289:29739-49.
46. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T, Hirao A, Suematsu M, Suda T. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 2013;12:49-61.
47. Kwon HS, Huang B, Unterman TG, Harris RA. Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Diabetes 2004;53:899-910.
48. Blackshear PJ, Holloway PA, Alberti KG. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem J 1974; 142:279-86.
49. McAllister A, Allison SP, Randle PJ. Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. Biochem J 1973;134:1067-81.
50. Relman AS. Lactic acidosis and a possible new treatment. N Engl J Med 1978;298:564-5.
51. Backshear PJ, Holloway PA, Alberti KG. Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Biochem J 1975;146:447-56.
52. Ho N, Coomber BL. Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxic human colorectal cancer cells. Exp Cell Res 2015;331: 73-81.
53. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010;2: 31ra4.
54. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 2010;120:253-60.
55. Ruggieri V, Agriesti F, Scrima R, Laurenzana I, Perrone D, Tataranni T, Mazzoccoli C, Lo Muzio L, Capitanio N, Piccoli C. Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment. Oncotarget 2015;6:1217-30.
56. Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 2013;3:38.
57. Bebernitz GR, Aicher TD, Stanton JL, Gao J, Shetty SS, Knorr DC, Strohschein RJ, Tan J, Brand LJ, Liu C, Wang WH, Vinluan CC, Kaplan EL, Dragland CJ, DelGrande D, Islam A, Lozito RJ, Liu X, Maniara WM, Mann WR. Anilides of (R)-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase. J Med Chem 2000;43:2248-57.
58. Mann WR, Dragland CJ, Vinluan CC, Vedananda TR, Bell PA, Aicher TD. Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors. Biochim Biophys Acta 2000;1480:283-92.
59. Yang Y, Shang P, Cheng C, Wang D, Yang P, Zhang F, Li T, Lu A, Zhao Y. Novel N-phenyl dichloroacetamide derivatives as anticancer reagents: design, synthesis and biological evaluation. Eur J Med Chem 2010;45:4300-6.
60. Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG. Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry 2006;45:402-15.
61. Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med 2013;5:175ra31.
62. Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis 2015 Jan 20 [Epub]. http://dx.doi.org/10.1007/s10545-014-9808-2.
63. Mayers RM, Leighton B, Kilgour E. PDH kinase inhibitors: a novel therapy for type II diabetes? Biochem Soc Trans 2005; 33(Pt 2):367-70.
64. Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure 2007;15:992-1004.
65. Kukimoto-Niino M, Tokmakov A, Terada T, Ohbayashi N, Fujimoto T, Gomi S, Shiromizu I, Kawamoto M, Matsusue T, Shirouzu M, Yokoyama S. Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4. Acta Crystallogr D Biol Crystallogr 2011;67(Pt 9):763-73.