PDK2: An Underappreciated Regulator of Liver Metabolism
Abstract
1. Introduction
2. The PDKs and PDH
3. Physiological Roles of PDKs
3.1. PDKs in Normal Physiology
3.2. Specific Roles for PDK2 in Normal Physiology:
4. Transcriptional Regulators of PDK2 Expression
5. PDK2 Inhibitors
5.1. Dichloroacetate
5.2. ATP Binding Site/PS10
5.3. Lipoyl-Binding Domain/AZD7545
6. Pathophysiological Roles of PDKs in Disease
6.1. PDK2 and the Metabolic Syndrome
PDK2 and Nutrient Excess
6.2. PDK2 in Cancer
PDK2 in Hepatocellular Carcinoma
7. PDKs in Inflammation, a Growing Area of Interest
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Bowker-Kinley, M.M.; Davis, I.W.; Wu, P.; Harris, A.R.; Popov, M.K. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem. J. 1998, 329, 191–196. [Google Scholar] [CrossRef] [PubMed]
- Warburg, O. On respiratory impairment in cancer cells. Science 1956, 124, 269–270. [Google Scholar] [PubMed]
- Warburg, O. On the Origin of Cancer Cells. Science 1956, 123, 309–314. [Google Scholar] [CrossRef]
- Stacpoole, P.W. Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer. J. Natl. Cancer Inst. 2017, 109. [Google Scholar] [CrossRef] [PubMed]
- Woolbright, B.L.; Rajendran, G.; Harris, R.A.; Taylor, J.A. Metabolic Flexibility in Cancer: Targeting the Pyruvate Dehydrogenase Kinase:Pyruvate Dehydrogenase Axis. Mol. Cancer Ther. 2019, 18, 1673–1681. [Google Scholar] [CrossRef]
- Klyuyeva, A.; Tuganova, A.; Kedishvili, N.Y.; Popov, K.M. Tissue-specific kinase expression and activity regulate flux through the pyruvate dehydrogenase complex. J. Biol. Chem. 2019, 294, 838–851. [Google Scholar] [CrossRef]
- Huang, B.; Wu, P.; Bowker-Kinley, M.M.; Harris, R.A. Regulation of Pyruvate Dehydrogenase Kinase Expression by Peroxisome Proliferator-Activated Receptor- Ligands, Glucocorticoids, and Insulin. Diabetes 2002, 51, 276–283. [Google Scholar] [CrossRef]
- Sugden, M.C.; Holness, M.J. Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate de-hydrogenase kinases. Arch Physiol. Biochem. 2006, 112, 139–149. [Google Scholar] [CrossRef]
- Jeoung, N.H.; Harris, R.A. Role of Pyruvate Dehydrogenase Kinase 4 in Regulation of Blood Glucose Levels. Korean Diabetes J. 2010, 34, 274–283. [Google Scholar] [CrossRef]
- Choiniere, J.; Wu, J.; Wang, L. Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins. Mol. Pharmacol. 2016, 91, 189–196. [Google Scholar] [CrossRef]
- Choiniere, J.; Lin, M.J.; Wang, L.; Wu, J. Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis. Liver Res. 2018, 2, 100–107. [Google Scholar] [CrossRef]
- Jeoung, N.H.; Rahimi, Y.; Wu, P.; Lee, W.N.P.; Harris, R.A. Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice. Biochem. J. 2012, 443, 829–839. [Google Scholar] [CrossRef]
- Linn, T.C.; Pettit, F.H.; Reed, L.J. Alpha-keto acid dehydrogenase complexes. X. Regulation of the activity of the pyruvate dehy-drogenase complex from beef kidney mitochondria by phosphorylation and dephosphorylation. Proc. Natl. Acad. Sci. USA 1969, 62, 234–241. [Google Scholar] [CrossRef]
- Roche, T.E.; Baker, J.C.; Yan, X.; Hiromasa, Y.; Gong, X.; Peng, T.; Dong, J.; Turkan, A.; Kasten, S.A. Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Prog. Nucleic Acid Res. Mol. Biol. 2001, 70, 33–75. [Google Scholar] [CrossRef] [PubMed]
- Shi, G.; McQuibban, G.A. The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism. Cell Rep. 2017, 18, 1458–1472. [Google Scholar] [CrossRef] [PubMed]
- Jeon, J.; Thoudam, T.; Choi, E.J.; Kim, M.; Harris, R.A.; Lee, I. Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases. J. Diabetes Investig. 2021, 12, 21–31. [Google Scholar] [CrossRef] [PubMed]
- Kato, M.; Li, J.; Chuang, J.L.; Chuang, D.T. Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol. Structure 2007, 15, 992–1004. [Google Scholar] [CrossRef] [PubMed]
- Klyuyeva, A.; Tuganova, A.; Popov, K.M. Allosteric Coupling in Pyruvate Dehydrogenase Kinase 2. Biochemistry 2008, 47, 8358–8366. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Sugden, M.C.; Holness, M.J. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydro-genase complex by PDKs. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E855–E862. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.-W.; Tchernyshyov, I.; Semenza, G.L.; Dang, C.V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006, 3, 177–185. [Google Scholar] [CrossRef] [PubMed]
- Sun, W.; Zhou, S.; Chang, S.S.; McFate, T.; Verma, A.; Califano, J.A. Mitochondrial Mutations Contribute to HIF1 Accumulation via Increased Reactive Oxygen Species and Up-regulated Pyruvate Dehydrogenease Kinase 2 in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 2009, 15, 476–484. [Google Scholar] [CrossRef]
- Dunford, E.C.; Herbst, E.A.; Jeoung, N.H.; Gittings, W.; Inglis, J.G.; Vandenboom, R.; Leblanc, P.J.; Harris, R.A.; Peters, S.J. PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: Effect of PDH kinase 1 compensation. Am. J. Physiol. Integr. Comp. Physiol. 2011, 300, R1487–R1493. [Google Scholar] [CrossRef]
- Fuller, S.J.; Randle, P.J. Reversible phosphorylation of pyruvate dehydrogenase in rat skeletal-muscle mitochondria. Effects of starvation and diabetes. Biochem. J. 1984, 219, 635–646. [Google Scholar] [CrossRef]
- Jeong, J.Y.; Jeoung, N.H.; Park, K.-G.; Lee, I.-K. Transcriptional Regulation of Pyruvate Dehydrogenase Kinase. Diabetes Metab. J. 2012, 36, 328–335. [Google Scholar] [CrossRef] [PubMed]
- Go, Y.; Jeong, J.Y.; Jeoung, N.H.; Jeon, J.-H.; Park, B.-Y.; Kang, H.-J.; Ha, C.-M.; Choi, Y.-K.; Lee, S.J.; Ham, H.J.; et al. Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis. Diabetes 2016, 65, 2876–2887. [Google Scholar] [CrossRef]
- Wu, P.; Sato, J.; Zhao, Y.; Jaskiewicz, J.; Popov, M.K.; Harris, A.R. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem. J. 1998, 329, 197–201. [Google Scholar] [CrossRef]
- Majer, M.; Popov, K.M.; Harris, R.A.; Bogardus, C.; Prochazka, M. Insulin Downregulates Pyruvate Dehydrogenase Kinase (PDK) mRNA: Potential Mechanism Contributing to Increased Lipid Oxidation in Insulin-Resistant Subjects. Mol. Genet. Metab. 1998, 65, 181–186. [Google Scholar] [CrossRef] [PubMed]
- Kwon, H.-S.; Huang, B.; Unterman, T.G.; Harris, R.A. Protein Kinase B- Inhibits Human Pyruvate Dehydrogenase Kinase-4 Gene Induction by Dexamethasone Through Inactivation of FOXO Transcription Factors. Diabetes 2004, 53, 899–910. [Google Scholar] [CrossRef] [PubMed]
- Furuyama, T.; Kitayama, K.; Yamashita, H.; Mori, N. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem. J. 2003, 375, 365–371. [Google Scholar] [CrossRef] [PubMed]
- Rena, G.; Guo, S.; Cichy, S.C.; Unterman, T.G.; Cohen, P. Phosphorylation of the Transcription Factor Forkhead Family Member FKHR by Protein Kinase B. J. Biol. Chem. 1999, 274, 17179–17183. [Google Scholar] [CrossRef] [PubMed]
- Zhang, W.; Patil, S.; Chauhan, B.; Guo, S.; Powell, D.R.; Le, J.; Klotsas, A.; Matika, R.; Xiao, X.; Franks, R.; et al. FoxO1 regulates multiple metabolic pathways in the liver: Effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 2006, 281, 10105–10117. [Google Scholar] [CrossRef] [PubMed]
- Degenhardt, T.; Saramäki, A.; Malinen, M.; Rieck, M.; Väisänen, S.; Huotari, A.; Herzig, K.H.; Müller, R.; Carlberg, C. Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta. J. Mol. Biol. 2007, 372, 341–355. [Google Scholar] [CrossRef] [PubMed]
- Byun, J.; Choi, Y.; Na Kang, Y.; Jang, B.K.; Kang, K.J.; Jeon, Y.H.; Lee, H.; Jeon, J.; Koo, S.; Jeong, W.; et al. Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology 2015, 61, 953–964. [Google Scholar] [CrossRef] [PubMed]
- Contractor, T.; Harris, C.R. p53 Negatively Regulates Transcription of the Pyruvate Dehydrogenase Kinase Pdk2. Cancer Res. 2012, 72, 560–567. [Google Scholar] [CrossRef] [PubMed]
- Roche, T.E.; Hiromasa, Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell. Mol. Life Sci. 2007, 64, 830–849. [Google Scholar] [CrossRef] [PubMed]
- Steussy, C.N.; Popov, K.M.; Bowker-Kinley, M.M.; Sloan, R.B., Jr.; Harris, R.A.; Hamilton, J.A. Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a serine protein kinase. J. Biol. Chem. 2001, 276, 37443–37450. [Google Scholar] [CrossRef]
- Brough, P.A.; Aherne, W.; Barril, X.; Borgognoni, J.; Boxall, K.; Cansfield, J.E.; Cheung, K.-M.J.; Collins, I.; Davies, N.G.M.; Drysdale, M.J.; et al. 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer. J. Med. Chem. 2008, 51, 196–218. [Google Scholar] [CrossRef] [PubMed]
- Moore, J.D.; Staniszewska, A.; Shaw, T.; D’Alessandro, J.; Davis, B.; Surgenor, A.; Baker, L.; Matassova, N.; Murray, J.; Macias, A.; et al. VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells. Oncotarget 2014, 5, 12862–12876. [Google Scholar] [CrossRef]
- Tuganova, A.; Yoder, M.D.; Popov, K.M. An Essential Role of Glu-243 and His-239 in the Phosphotransfer Reaction Catalyzed by Pyruvate Dehydrogenase Kinase. J. Biol. Chem. 2001, 276, 17994–17999. [Google Scholar] [CrossRef]
- Sharma, S.V.; Agatsuma, T.; Nakano, H. Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol. Oncogene 1998, 16, 2639–2645. [Google Scholar] [CrossRef]
- Tso, S.-C.; Qi, X.; Gui, W.-J.; Wu, C.-Y.; Chuang, J.L.; Wernstedt-Asterholm, I.; Morlock, L.K.; Owens, K.R.; Scherer, P.E.; Williams, N.S.; et al. Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket. J. Biol. Chem. 2014, 289, 4432–4443. [Google Scholar] [CrossRef] [PubMed]
- Pratt, M.L.; Roche, T.E. Mechanism of pyruvate inhibition of kidney pyruvate dehydrogenasea kinase and synergistic inhibition by pyruvate and ADP. J. Biol. Chem. 1979, 254, 7191–7196. [Google Scholar] [CrossRef]
- Knoechel, T.R.; Tucker, A.D.; Robinson, C.M.; Phillips, C.; Taylor, W.; Bungay, P.J.; Kasten, S.A.; Roche, T.E.; Brown, D.G. 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, 402–415. [Google Scholar] [CrossRef]
- Holness, M.; Sugden, M. Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem. Soc. Trans. 2003, 31, 1143–1151. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Kato, M.; Chuang, D.T. Pivotal Role of the C-terminal DW-motif in Mediating Inhibition of Pyruvate Dehydrogenase Kinase 2 by Dichloroacetate. J. Biol. Chem. 2009, 284, 34458–34467. [Google Scholar] [CrossRef] [PubMed]
- Whitehouse, S.; Cooper, R.H.; Randle, P.J. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem. J. 1974, 141, 761–774. [Google Scholar] [CrossRef]
- Babu, E.; Ramachandran, S.; Coothankandaswamy, V.; Elangovan, S.; Prasad, P.D.; Ganapathy, V.; Thangaraju, M. Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. Oncogene 2011, 30, 4026–4037. [Google Scholar] [CrossRef]
- James, M.O.; Jahn, S.C.; Zhong, G.; Smeltz, M.G.; Hu, Z.; Stacpoole, P.W. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol. Ther. 2017, 170, 166–180. [Google Scholar] [CrossRef]
- Jahn, S.C.; Solayman, M.H.M.; Lorenzo, R.J.; Langaee, T.; Stacpoole, P.W.; James, M.O. GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate. Biochim. Biophys. Acta Gen. Subj. 2016, 1860, 1202–1210. [Google Scholar] [CrossRef]
- Stacpoole, P.W. The pharmacology of dichloroacetate. Metabolism 1989, 38, 1124–1144. [Google Scholar] [CrossRef]
- Stacpoole, P.W.; Nagaraja, N.V.; Hutson, A.D. Efficacy of dichloroacetate as a lactate-lowering drug. J. Clin. Pharmacol. 2003, 43, 683–691. [Google Scholar] [CrossRef] [PubMed]
- Shroads, A.L.; Langaee, T.; Coats, B.S.; Kurtz, T.L.; Bullock, J.R.; Weithorn, D.; Gong, Y.; Wagner, D.A.; Ostrov, D.A.; Johnson, J.A.; et al. Human Polymorphisms in the Glutathione Transferase Zeta 1/Maleylacetoacetate Isomerase Gene Influence the Toxicokinetics of Dichloroacetate. J. Clin. Pharmacol. 2012, 52, 837–849. [Google Scholar] [CrossRef] [PubMed]
- Dunbar, E.M.; Coats, B.S.; Shroads, A.L.; Langaee, T.; Lew, A.; Forder, J.R.; Shuster, J.J.; Wagner, D.A.; Stacpoole, P.W. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Investig. New Drugs 2014, 32, 452–464. [Google Scholar] [CrossRef] [PubMed]
- Stacpoole, P.W.; Martyniuk, C.J.; James, M.O.; Calcutt, N.A. Dichloroacetate-induced peripheral neuropathy. Int. Rev. Neurobiol. 2019, 145, 211–238. [Google Scholar] [CrossRef]
- Tataranni, T.; Agriesti, F.; Pacelli, C.; Ruggieri, V.; Laurenzana, I.; Mazzoccoli, C.; Della-Sala, G.; Panebianco, C.; Pazienza, V.; Capitanio, N.; et al. Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines. Cells 2019, 8, 478. [Google Scholar] [CrossRef] [PubMed]
- Tataranni, T.; Piccoli, C. Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications. Oxidative Med. Cell. Longev. 2019, 2019, 1–14. [Google Scholar] [CrossRef]
- Chen, J.; Guccini, I.; di Mitri, D.; Brina, D.; Revandkar, A.; Sarti, M.; Pasquini, E.; Alajati, A.; Pinton, S.; Losa, M.; et al. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat. Genet. 2018, 50, 219–228. [Google Scholar] [CrossRef]
- Zachar, Z.; Marecek, J.; Maturo, C.; Gupta, S.; Stuart, S.D.; Howell, K.; Schauble, A.; Lem, J.; Piramzadian, A.; Karnik, S.; et al. Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. J. Mol. Med. 2011, 89, 1137–1148. [Google Scholar] [CrossRef]
- Newsholme, E.A.; Crabtree, B.; Ardawi, M.S.M. The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci. Rep. 1985, 5, 393–400. [Google Scholar] [CrossRef]
- Dutta, R.; Inouye, M. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci. 2000, 25, 24–28. [Google Scholar] [CrossRef]
- Tso, S.-C.; Lou, M.; Wu, C.-Y.; Gui, W.-J.; Chuang, J.L.; Morlock, L.K.; Williams, N.S.; Wynn, R.M.; Qi, X.; Chuang, D.T. Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors. J. Med. Chem. 2017, 60, 1142–1150. [Google Scholar] [CrossRef] [PubMed]
- Morrell, J.; Orme, J.; Butlin, R.; Roche, T.; Mayers, R.; Kilgour, E. AZD7545 is a selective inhibitor of pyruvate dehydrogenase kinase 2. Biochem. Soc. Trans. 2003, 31, 1168–1170. [Google Scholar] [CrossRef] [PubMed]
- Mayers, R.; Butlin, R.; Kilgour, E.; Leighton, B.; Martin, D.; Myatt, J.; Orme, J.; Holloway, B. AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats. Biochem. Soc. Trans. 2003, 31, 1165–1167. [Google Scholar] [CrossRef] [PubMed]
- Wynn, R.M.; Kato, M.; Chuang, J.L.; Tso, S.-C.; Li, J.; Chuang, D.T. Pyruvate Dehydrogenase Kinase-4 Structures Reveal a Metastable Open Conformation Fostering Robust Core-free Basal Activity. J. Biol. Chem. 2008, 283, 25305–25315. [Google Scholar] [CrossRef] [PubMed]
- Arrese, M.; Cabrera, D.; Kalergis, A.M.; Feldstein, A.E. Innate Immunity and Inflammation in NAFLD/NASH. Dig. Dis. Sci. 2016, 61, 1294–1303. [Google Scholar] [CrossRef] [PubMed]
- Rowe, I.A.; Wong, V.W.-S.; Loomba, R. Treatment candidacy for pharmacologic therapies for NASH. Clin. Gastroenterol. Hepatol. 2021. [Google Scholar] [CrossRef] [PubMed]
- Wu, C.Y.; Tso, S.C.; Chuang, J.L.; Gui, W.J.; Lou, M.; Sharma, G.; Khemtong, C.; Qi, X.; Wynn, R.M.; Chuang, D.T. Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipo-genesis in diet-induced obese mice. Mol. Metab. 2018, 12, 12–24. [Google Scholar] [CrossRef]
- Lassailly, G.; Caiazzo, R.; Ntandja-Wandji, L.-C.; Gnemmi, V.; Baud, G.; Verkindt, H.; Ningarhari, M.; Louvet, A.; Leteurtre, E.; Raverdy, V.; et al. Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology 2020, 159, 1290–1301. [Google Scholar] [CrossRef] [PubMed]
- Bonnet, S.; Archer, S.L.; Allalunis-Turner, J.; Haromy, A.; Beaulieu, C.; Thompson, R.; Lee, C.T.; Lopaschuk, G.D.; 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 2007, 11, 37–51. [Google Scholar] [CrossRef] [PubMed]
- Heiden, M.G.V.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033. [Google Scholar] [CrossRef]
- Wallace, D.C. Mitochondria and cancer. Nat. Rev. Cancer 2012, 12, 685–698. [Google Scholar] [CrossRef] [PubMed]
- Shang, H.; Zheng, J.; Tong, J. Integrated analysis of transcriptomic and metabolomic data demonstrates the significant role of pyruvate carboxylase in the progression of ovarian cancer. Aging 2020, 12, 21874–21889. [Google Scholar] [CrossRef]
- Lin, Q.; He, Y.; Wang, X.; Zhang, Y.; Hu, M.; Guo, W.; He, Y.; Zhang, T.; Lai, L.; Sun, Z.; et al. Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression. Adv. Sci. 2020, 7, 1903483. [Google Scholar] [CrossRef] [PubMed]
- Moreno-Sánchez, R.; Marín-Hernández, Á.; Gallardo-Pérez, J.C.; Pacheco-Velázquez, S.C.; Robledo-Cadena, D.X.; Padilla-Flores, J.A.; Saavedra, E.; Rodríguez-Enríquez, S. Physiological Role of Glutamate Dehydrogenase in Cancer Cells. Front. Oncol. 2020, 10, 429. [Google Scholar] [CrossRef] [PubMed]
- Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; et al. Sorafenib in Advanced Hepatocellular Carcinoma. N. Engl. J. Med. 2008, 359, 378–390. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.H.; de Berardinis, R.J.; Wen, X.; Corbin, I.R.; Sherry, A.D.; Malloy, C.R.; Jin, E.S. Active pyruvate dehydrogenase and impaired gluconeogenesis in orthotopic hepatomas of rats. Metabolism 2019, 101, 153993. [Google Scholar] [CrossRef]
- Fekir, K.; Dubois-Pot-Schneider, H.; Désert, R.; Daniel, Y.; Glaise, D.; Rauch, C.; Morel, F.; Fromenty, B.; Musso, O.; Cabillic, F.; et al. Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemo-resistance. Cancer Res. 2019, 79, 1869–1883. [Google Scholar] [CrossRef]
- Dai, Y.; Xiong, X.; Huang, G.; Liu, J.; Sheng, S.; Wang, H.; Qin, W. Dichloroacetate Enhances Adriamycin-Induced Hepatoma Cell Toxicity In Vitro and In Vivo by Increasing Reactive Oxygen Species Levels. PLoS ONE 2014, 9, e92962. [Google Scholar] [CrossRef]
- Shen, Y.-C.; Ou, D.-L.; Hsu, C.; Lin, K.-L.; Chang, C.-Y.; Lin, C.-Y.; Liu, S.-H.; Cheng, A.-L. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br. J. Cancer 2012, 108, 72–81. [Google Scholar] [CrossRef]
- Meng, G.; Li, B.; Chen, A.; Zheng, M.; Xu, T.; Zhang, H.; Dong, J.; Wu, J.; Yu, D.; Wei, J. Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma. Br. J. Cancer 2020, 122, 111–120. [Google Scholar] [CrossRef]
- Palmer, C.S.; Ostrowski, M.; Balderson, B.; Christian, N.; Crowe, S.M. Glucose Metabolism Regulates T Cell Activation, Differentiation, and Functions. Front. Immunol. 2015, 6, 1. [Google Scholar] [CrossRef] [PubMed]
- Menk, A.V.; Scharping, N.E.; Moreci, R.S.; Zeng, X.; Guy, C.; Salvatore, S.; Bae, H.; Xie, J.; Young, H.A.; Wendell, S.G.; et al. Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Rep. 2018, 22, 1509–1521. [Google Scholar] [CrossRef] [PubMed]
- Min, B.-K.; Park, S.; Kang, H.-J.; Kim, D.W.; Ham, H.J.; Ha, C.-M.; Choi, B.-J.; Lee, J.Y.; Oh, C.J.; Yoo, E.K.; et al. Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype. Front. Immunol. 2019, 10, 944. [Google Scholar] [CrossRef] [PubMed]
- Tan, Z.; Xie, N.; Cui, H.; Moellering, D.R.; Abraham, E.; Thannickal, V.J.; Liu, G. Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism. J. Immunol. 2015, 194, 6082–6089. [Google Scholar] [CrossRef]
- Galvan-Pena, S.; O’Neill, L.A. Metabolic reprograming in macrophage polarization. Front. Immunol. 2014, 5, 420. [Google Scholar]
- Na, Y.R.; Jung, D.; Song, J.; Park, J.-W.; Hong, J.J.; Seok, S.H. Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages. J. Mol. Cell Biol. 2020, 12, 543–555. [Google Scholar] [CrossRef]
- Woolbright, B.L.; Jaeschke, H. Alcoholic Hepatitis: Lost in Translation. J. Clin. Transl. Hepatol. 2017, 6, 1–8. [Google Scholar] [CrossRef]
Inhibitor | Target | Efficacy | Notes | Refs |
---|---|---|---|---|
Dichloroacetate | pyruvate binding site | millimolar | common inhibitor | [4] |
PS10 | ATP binding site | micromolar | high specificity for PDKs 2 and 4, and to a lesser degree PDK1 | [36] |
azd7545 | PDH E2 lipoyl domain | micromolar | higher specificity for PDK1 and PDK2 | [37,38] |
2-chloropropionate | pyruvate binding site | millimolar | DCA analog | [4] |
radicicol | ATP binding site | micromolar | also inhibits HSP90 | [39] |
VER-246608 | ATP binding site | millimolar | pan-isoform inhibitor | [40] |
Compound 17, PS10 derivative | ATP binding site inhibitor | micromolar | poorly defined thus far | [36,41] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Woolbright, B.L.; Harris, R.A. PDK2: An Underappreciated Regulator of Liver Metabolism. Livers 2021, 1, 82-97. https://doi.org/10.3390/livers1020008
Woolbright BL, Harris RA. PDK2: An Underappreciated Regulator of Liver Metabolism. Livers. 2021; 1(2):82-97. https://doi.org/10.3390/livers1020008
Chicago/Turabian StyleWoolbright, Benjamin L., and Robert A. Harris. 2021. "PDK2: An Underappreciated Regulator of Liver Metabolism" Livers 1, no. 2: 82-97. https://doi.org/10.3390/livers1020008
APA StyleWoolbright, B. L., & Harris, R. A. (2021). PDK2: An Underappreciated Regulator of Liver Metabolism. Livers, 1(2), 82-97. https://doi.org/10.3390/livers1020008