title: Mitochondrial DNA damage is sensitive to exogenous H(2)O(2) but independent of cellular ROS production in prostate cancer cells.
abstract: 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 H(2)O(2) induces preferential cytotoxicity in aggressive prostate cancer than normal cells; a cascade production of cellular ROS, composed mainly of superoxide (O(2)(-)), is shown to be a critical determinant of H(2)O(2)-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 H(2)O(2) exposure in both cancer and normal cell lines. Moreover, we demonstrate for the first time that the sensitive mtDNA damage response to exogenous H(2)O(2) 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.
authors.affiliation: Department of Surgery, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Sam W
authors.initials: SW
authors.lastname: Chan
authors.forename: Phuong-Nam
authors.initials: PN
authors.lastname: Nguyen
authors.forename: David
authors.initials: D
authors.lastname: Ayele
authors.forename: Simone
authors.initials: S
authors.lastname: Chevalier
authors.forename: Armen
authors.initials: A
authors.lastname: Aprikian
authors.forename: Junjian Z
authors.initials: JZ
authors.lastname: Chen
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D004272:DNA, Mitochondrial; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress / Q000235:genetics*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D006861:Hydrogen Peroxide