Download 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 !