Environment, mitochondria and metabolism
Are Mitochondria the cell Achilles' heel accounting for the transformation of normal cells into cancerous ones under the influence of carcinogens?
A major discovery that distinguishes cancer cells from normal cells is that many cancer cells mainly use glycolysis in their cytoplasm to generate ATP. This phenomenon of so-called aerobic glycolysis relates to the Warburg effect which is a hallmark of cancer cell metabolism (Hsu and Sabatini, Cancer cell metabolism: Warburg and beyond, Cell. 2008 Sep 5;134(5):703-7). This effect is now well understood since it has been clearly established that cancer cells are associated with mitochondrial dysfunction and mutations in mitochondrial DNA (mt DNA) (Copeland et al, Cancer Mitochondrial DNA alterations in cancer, Cancer Invest. 2002;20(4):557-69;Wallace,Mitochondria and cancer: Warburg addressed, Cold Spring Harb Symp Quant Biol.2005;70:363-74). Excessive glycation of mitochondrial proteins, lipids and mt DNA, due to mitochondria-associated carbonyl stress have been shown to contribute to mitochondrial dysfunction, and mt DNA mutations (Pun and Murphy, Pathological significance of mitochondrial glycation, Int J Cell Biol.2012;2012:843505.).
In addition, the production of free radicals in excess in the vicinity of mt DNA by dys-functioning mitochondria and the absence of protective histones in mt DNA (Baynes, The Maillard hypothesis on aging: time to focus on DNA, Ann N Y Acad Sci.2002 Apr;959:360-7) may explain why the mitochondrial genome is much more susceptible both to carbonyl stress and oxidative stress than the nuclear genome and thus undergoes a higher rate of mutations (Yakes and Van Houten,Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress, Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):514-9). Moreover it has been shown that epigenetic and/or mutagenic changes in cancer cells can induce: (1) overexpression of type 2 hexokinase (Goel et al,Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression, J Biol Chem.2003 Apr 25;278(17):15333-40. Epub 2003 Feb); (2) activation of normally insulin-regulated glucose membrane receptors, especially GLUT1, GLUT3 and GLUT5 (Merral et al, Cell Signal 1993), leading extracellular glucose to penetrate easily into cancer cells; and finally (3) overexpression of all glycolytic enzymes in aerobic and anaerobic conditions, causing intracellular glucose to be actively metabolized by cancer cells whatever the intra-tumoral oxygenic conditions are (Hanahan and Weinberg,Hallmarks of cancer: the next generation, Cell.2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013).
Taking into consideration the metabolic characteristics of cancer cells in comparison with those of normal cells, a new cancer cell metabolic marker has been discovered allowing the identification and use of a new blood test for diagnosis, prognosis and treatment of all types of cancer (unpublished data).
Four ECERI centers are presently involved in the develompent of this research : the ARTAC research center based in Paris, which is the initiator of the discovery, the Mediterranian Center for Molecular Medicine (C3M) in Nice University, the Nancy University Hospital (France) and the Metastasis Research Laboratory in Liège University (Belgium).
