Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(10):2166-2171; doi:10.1093/carcin/bgm093
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Bcl-2 over-expression promotes genomic instability by inhibiting apoptosis of cells exposed to hydrogen peroxide
1 Free Radical Research Group, Department of Pathology, Christchurch School of Medicine & Health Sciences, University of Otago, PO Box 4345, Christchurch, New Zealand
2 School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
* To whom correspondence should be addressed. Tel: +64 3 364 1524; Fax: +64 3 364 1083; Email: mark.hampton{at}chmeds.ac.nz
The anti-apoptotic oncogene bcl-2 is hypothesized to increase the antioxidant status of cells, thereby protecting them from oxidative stress. In this study, we examined hydrogen peroxide (H2O2)-mediated oxidative stress in Jurkat T lymphoma cells. Over-expression of Bcl-2 did not inhibit cytotoxicity at doses of H2O2 that caused necrosis (>200 µM), but it did block cell death at apoptotic doses (<200 µM). However, these cells exhibited the same initial level of protein and lipid oxidation following exposure to H2O2 as the parental cells, indicating that the anti-apoptotic activity is not associated with general antioxidant properties. Bcl-2 expression was able to protect against secondary protein carbonyl formation, which was linked to lysosome stabilization. Assessment of micronuclei formation in cells over-expressing Bcl-2 showed evidence of increased genomic instability, consistent with the impairment of apoptosis in damaged cells. We conclude that while Bcl-2 can block cytotoxicity associated with apoptosis-inducing levels of oxidative stress, it does not protect the cells from the stress itself. Bcl-2 may promote tumourigenesis by preventing the removal of oxidatively damaged cells.
Abbreviations: AMC, 7-amino-4-methylcoumarin; AO, acridine orange; CBMN, cytokinesis-block micronuclei; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H2O2, hydrogen peroxide; 5-IAF, 5-iodoacetamidofluorescein; PBS, phosphate-buffered saline
Received December 21, 2006; revised April 3, 2007; accepted April 4, 2007.
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