As(III) inhibits ultraviolet radiation-induced cyclobutane pyrimidine dimer repair via generation of nitric oxide in human keratinocytes.
Inorganic arsenic enhances skin tumor formation when combined with other carcinogens including ultraviolet radiation (UVR). The inhibition of DNA damage repair by arsenic has been hypothesized to contribute to the cocarcinogenic activities of arsenic observed in vivo. Cyclobutane pyrimidine dimers (CPDs) are an important mutagenic UVR photoproduct and implicated in the genesis of nonmelanoma skin cancer. The current study demonstrates that low concentrations of arsenite (As(III)) inhibit UVR-induced CPD repair in a human keratinocyte cell line via nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Following As(III) treatment, NO production and iNOS expression are elevated. Little is known about regulation of iNOS by As(III) and further investigations indicated that p38 mitogen-activated protein kinase (p38 MAPK) and NF-kappaB are required for As(III) induction of iNOS expression. This As(III)-stimulated signaling cascade was involved in inhibition of UVR-induced CPD repair as disruption of p38 MAPK activity and NF-kappaB nuclear translocation counteracted the effects of As(III) on CPD repair. Selective inhibition of iNOS ameliorated As(III) inhibition of CPD repair, thereby suggesting that iNOS is a downstream mediator of As(III) activity. These findings provide evidence that an As(III)-stimulated signal transduction cascade culminating in elevated iNOS expression and NO generation is an underlying mechanism for inhibition of UVR-induced DNA damage repair by arsenic.
Ding
Wei
W
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
Hudson
Laurie G
LG
Sun
Xi
X
Feng
Changjian
C
Liu
Ke Jian
KJ
D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014466:Ultraviolet Rays / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D018053:Arsenites; D002273:Carcinogens; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011740:Pyrimidine Dimers; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; C015001:arsenite