Transcript TCA Cycle
Cancer Metabolism & Cancer Genetics Presented by Sungmin Lee Biochemistry Lab. Overview of metabolism Acyl CoA Lipid Glyoxylate Cycle Electron Transport Chain Glycolysis TCA Cycle NADH, FADH2 Glucose R Carbon skeleton Amino group Amino acid Asp-Argsuccinate Cycle ATP Urea Cycle Altered cancer metabolism Glycolysis Amino acid cycle β-oxidation doi:10.1038/nrc.2016.85 Cancer glycolysis - Warburg effect Warburg effect • Increased glucose uptake • Increased glycolysis • Decreased use of pyruvate to TCA cycle • Increased lactate production • Increased angiogenesis . . . Warburg effect Cancer glycolysis - GLUT Cancers 2013, 5(4), 1469-1484 Clin Cancer Res. 2013 Nov 1;19(21):5835-41 Cancer glycolysis - GLUT • Oncogenic mutation & hypoxic condition resulted in up-regulation of glycolytic enzymes. FEBS Lett. 2007 Jul 31;581(19):3582-91 Cancer glycolysis - PHGDH • Metabolite flux 3PG to serine biosynthesis increased availability of glutamine/α-KG to TCA cycle. • It shows that suppression of TCA cycle does not always contribute to cancer progression. Nature. 2011 Aug 18;476(7360):346-50. Relapse Free Survival Probability Cancer glycolysis - PHGDH Time (months) Cell. 2013 May 9;153(4):840-54. Cancer Res. 2016 Aug 1;76(15):4430-42 • The importance of the PHGDH as a therapeutic target is suggested by current studies. Cancer glycolysis - PKM2 Clin Cancer Res. 2012 Oct 15;18(20):5554-61 Nature, 2014, 508(10):158-159 Cancer glycolysis - PKM2 Clin Cancer Res. 2012 Oct 15;18(20):5554-61 Cancer Lett. 2015 Jan 28;356(2 Pt A):184-91 Cancer amino acid cycle - ASS1 • Decreased expression of ASS1 resulted in deficiency of arginine (= Arginine auxotrophy) Int. J. Cancer, 2009, 125:1454-63 Cancer amino acid cycle - ASS1 Int J Cancer. 2010 Jun 15;126(12):2762-72 PLoS One. 2016 Mar 16;11(3):e0150044. • Arginine auxotrophy can induce not only alteration of metabolic intermediates but induce chemoresistance including platinum resistance which firstly reported ASS1-related resistance. Cancer amino acid cycle - GLO1 Oncogene (2015) 34:1196–1206 Exp. Cell Res. 2012, 318:152-159 Cancer fat metabolism - FASN Nat Rev Cancer. 2007 Oct;7(10):763-77. Cancer fat metabolism - FASN Evid Based Complement Alternat Med. 2014;2014:232946 Nat Rev Cancer. 2007 Oct;7(10):763-77. Cancer fat metabolism - IDHs R132H Clin Cancer Res, 2012 18(20):5562-5571 Acta Neuropathol 2008 116:597–602 Cancer fat metabolism - IDHs • D-2HG can induce epigenetic alteration in cancer including methylation and histone modification to morph cells to cancer stem cell-like phenotypes. • According to the reason above, D-2HG is called by “oncometabolite” Cancer therapies Metformin : activates of AMPK and reduce glycolysis CBR-5884 : PHDGH inhibitor α-Methyl-DL-aspartic acid : ASS1 specific inhibitor NCT-502 : currently suggested PHDGH inhibitor TVB-3166 : FASN specific inhibitor Nat Chem Biol. 2016 Jun;12(6):452-8 PLoS One. 2015 Dec 11;10(12):e0144648 Thank you for your attention !