title: Poly(ADP-ribose) polymerase-1 inhibition by arsenite promotes the survival of cells with unrepaired DNA lesions induced by UV exposure.
abstract: Human arsenic exposure is associated with increased risk of skin cancer, and arsenite greatly enhances ultraviolet (UV)-induced skin tumors in a mouse model of carcinogenesis. Inhibition of DNA repair is one proposed mechanism for the observed cocarcinogenicity. We have previously demonstrated that low concentrations of arsenite inhibit poly(ADP-ribose) polymerase (PARP)-1, thus interfering with DNA repair process triggered by UV radiation. Because overactivation of PARP-1 often leads to apoptotic cell death, and unrepaired DNA lesions promote genomic instability and carcinogenesis, we hypothesized that inhibition of PARP-1 by arsenic may promote the survival of potentially "initiated carcinogenic cells," i.e., cells with unrepaired DNA lesions. In the present study, we tested this hypothesis on UV-challenged HaCat cells. Cells were pretreated with 2μM arsenite for 24 h before UV exposure. Outcome parameters included apoptotic death rate, PARP-1 activation, apoptotic molecules, and retention of DNA lesions. UV exposure induced PARP-1 activation and associated poly(ADP-ribose) production, apoptosis-inducing factor release, cytochrome C release, and caspases activation, which led to apoptotic death in HaCat cells. Pretreatment with 2μM arsenite significantly inhibited UV-induced cell death as well as the associated molecular events. Notably, knockdown of PARP-1 with small interfering RNA completely abolished the antagonism of arsenite. Furthermore, arsenite pretreatment led to long-term retention of UV-induced cyclobutane pyrimidine dimers. Together, these results suggest that low concentration of arsenite reduces UV-induced apoptosis via inhibiting PARP-1, thus promoting the survival of cells with unrepaired DNA lesions, which may be an important mechanism underlying arsenic cocarcinogenic action.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA.
authors.forename: Xu-Jun
authors.initials: XJ
authors.lastname: Qin
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.forename: Ying-Na
authors.initials: YN
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Sun
authors.forename: Chun-Xu
authors.initials: CX
authors.lastname: Hai
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D018053:Arsenites / Q000633:toxicity*; D061945:Caspase Inhibitors; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000528:radiation effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011830:Radiation Effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D018053:Arsenites; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C015001:arsenite