Mitochondrial DNA damage is sensitive to exogenous H2O2 but independent of cellular ROS production in prostate cancer cells

作者：Chan Sam W; Phuong Nam Nguyen; Ayele David; Chevalier Simone; Aprikian Armen; Chen Junjian Z^*

来源：Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 2011, 716(1-2): 40-50.

DOI：10.1016/j.mrfmmm.2011.07.019

• mtDNA damage
• Prostate cancer
• ROS
• Oxidative stress
• Supercoiling-sensitive PCR

Intrinsic oxidative stress through enhanced production of reactive oxygen species (ROS) in prostate and other cancers may contribute to cancer progression due to its stimulating effect on cancer growth. In this study, we investigate differential responses to exogenous oxidative stimuli between aggressive prostate cancer and normal cell lines and explore potential mechanisms through interactions between cytotoxicity, cellular ROS production and oxidative DNA damage. The circular, multi-copy mitochondrial DNA (mtDNA) is used as a sensitive surrogate to oxidative DNA damage. We demonstrate that exogenous H2O2 induces preferential cytotoxicity in aggressive prostate cancer than normal cells; a cascade production of cellular ROS, composed mainly of superoxide (O-2(center dot-)), is shown to be a critical determinant of H2O2-induced selective toxicity in cancer cells. In contrast, mtDNA damage and copy number depletion, as measured by a novel two-phase strategy of the supercoiling-sensitive qPCR method, are very sensitive to exogenous H2O2 exposure in both cancer and normal cell lines. Moreover, we demonstrate for the first time that the sensitive mtDNA damage response to exogenous H2O2 is independent of secondary cellular ROS production triggered by several ROS modulators regardless of cell phenotypes. These new findings suggest different mechanisms underpinning cytotoxicity and DNA damage induced by oxidative stress and a susceptible phenotype to oxidative injury associated with aggressive prostate cancer cells in vitro.

• 出版日期2011-11-1