Modeling core metabolism in cancer cells: surveying the topology underlying the Warburg effect.
BACKGROUND
Alterations on glucose consumption and biosynthetic activity of amino acids, lipids and nucleotides are metabolic changes for sustaining cell proliferation in cancer cells. Irrevocable evidence of this fact is the Warburg effect which establishes that cancer cells prefers glycolysis over oxidative phosphorylation to generate ATP. Regulatory action over metabolic enzymes has opened a new window for designing more effective anti-cancer treatments. This enterprise is not trivial and the development of computational models that contribute to identifying potential enzymes for breaking the robustness of cancer cells is a priority.


RESULTS
This work presents a constraint-base modeling of the most experimentally studied metabolic pathways supporting cancer cells: glycolysis, TCA cycle, pentose phosphate, glutaminolysis and oxidative phosphorylation. To evaluate its predictive capacities, a growth kinetics study for Hela cell lines was accomplished and qualitatively compared with in silico predictions. Furthermore, based on pure computational criteria, we concluded that a set of enzymes (such as lactate dehydrogenase and pyruvate dehydrogenase) perform a pivotal role in cancer cell growth, findings supported by an experimental counterpart.


CONCLUSIONS
Alterations on metabolic activity are crucial to initiate and sustain cancer phenotype. In this work, we analyzed the phenotype capacities emerged from a constructed metabolic network conformed by the most experimentally studied pathways sustaining cancer cell growth. Remarkably, in silico model was able to resemble the physiological conditions in cancer cells and successfully identified some enzymes currently studied by its therapeutic effect. Overall, we supplied evidence that constraint-based modeling constitutes a promising computational platform to: 1) integrate high throughput technology and establish a crosstalk between experimental validation and in silico prediction in cancer cell phenotype; 2) explore the fundamental metabolic mechanism that confers robustness in cancer; and 3) suggest new metabolic targets for anticancer treatments. All these issues being central to explore cancer cell metabolism from a systems biology perspective.
Resendis-Antonio
Osbaldo
O
Centro de Ciencias Genomicas-Universidad Nacional Autónoma de México, Cuernavaca, México. resendis@ccg.unam.mx
Checa
Alberto
A
Encarnación
Sergio
S
D049109:Cell Proliferation; D002952:Citric Acid Cycle; D019295:Computational Biology; D006019:Glycolysis; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010085:Oxidative Phosphorylation; D010427:Pentose Phosphate Pathway; D010641:Phenotype
Nat Rev Microbiol. 2009 Feb;7(2):129-43
19116616
Cell. 2008 Sep 5;134(5):703-7
18775299
Cancer Res. 2010 Jan 1;70(1):12-3
20028868
Science. 2009 Sep 18;325(5947):1544-9
19762644
Science. 2009 May 22;324(5930):1029-33
19460998
Carcinogenesis. 2010 Jan;31(1):2-8
19861649
Curr Opin Genet Dev. 2008 Feb;18(1):54-61
18387799
Appl Environ Microbiol. 1994 Oct;60(10):3724-31
7986045
Nat Rev Cancer. 2009 Oct;9(10):691-700
19759539
Cell. 2000 Jan 7;100(1):57-70
10647931
PLoS One. 2009;4(3):e4967
19305506
Trends Biochem Sci. 1999 Feb;24(2):68-72
10098401
Int J Cancer. 2006 Dec 15;119(12):2733-41
17019714
Science. 2006 Jun 16;312(5780):1650-3
16728594
Nat Rev Microbiol. 2004 Nov;2(11):886-97
15494745
PLoS Comput Biol. 2007 Oct;3(10):1887-95
17922569
J Biol Chem. 2002 Aug 2;277(31):28058-64
12006566
Nat Protoc. 2010 Jan;5(1):93-121
20057383
Cancer Cell. 2005 Oct;8(4):311-21
16226706
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1777-82
17267599
Science. 2006 May 26;312(5777):1158-9
16728625
Nat Rev Cancer. 2004 Nov;4(11):891-9
15516961
Nature. 2008 Mar 13;452(7184):230-3
18337823
FEBS Lett. 2009 Dec 17;583(24):3900-4
19769971
Curr Opin Cell Biol. 2006 Dec;18(6):598-608
17046224
Nat Protoc. 2007;2(3):727-38
17406635
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
18032601
Nat Rev Cancer. 2005 Nov;5(11):857-66
16327764
Nat Biotechnol. 2002 Mar;20(3):243-9
11875424
Clin Cancer Res. 2006 Oct 1;12(19):5632-40
17020965
Biophys J. 2004 Oct;87(4):2172-86
15454420
Nat Rev Genet. 2004 Nov;5(11):826-37
15520792
Nat Biotechnol. 2008 Jun;26(6):659-67
18536691
J Biol Chem. 2008 Aug 15;283(33):22700-8
18541534
J Theor Biol. 2004 Jun 21;228(4):437-47
15178193
Genes Dev. 2009 Mar 1;23(5):537-48
19270154
Nature. 2004 May 6;429(6987):92-6
15129285
Cancer Res. 2005 Jan 15;65(2):613-21
15695406
Science. 1956 Feb 24;123(3191):309-14
13298683
Cancer Cell. 2006 Jun;9(6):425-34
16766262