title: Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC.
abstract: Chronic exposure to arsenic, most often through contaminated drinking water, has been linked to several types of cancer in humans, including skin and lung cancer. However, the mechanisms underlying its role in causing cancer are not well understood. There is evidence that exposure to arsenic can enhance the carcinogenicity of UV light in inducing skin cancers and may enhance the carcinogenicity of tobacco smoke in inducing lung cancers. The nucleotide excision repair (NER) pathway removes different types of DNA damage including those produced by UV light and components of tobacco smoke. The aim of the present study was to investigate the effect of sodium arsenite on the NER pathway in human lung fibroblasts (IMR-90 cells) and primary mouse keratinocytes. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts (6-4 PP) and cyclobutane pyrimidine dimers (CPDs). We find a concentration-dependent inhibition of the removal of 6-4 PPs and CPDs in both cell types treated with arsenite. Treatment of both cell types with arsenite resulted in a significant reduction in the abundance of XPC, a protein that is critical for DNA damage recognition in NER. The abundance of RNA expressed from several key NER genes was also significantly reduced by treatment of IMR-90 cells with arsenite. Finally, treatment of IMR-90 cells with MG-132 abrogated the reduction in XPC protein, suggesting an involvement of the proteasome in the reduction of XPC protein produced by treatment of cells with arsenic. The inhibition of NER by arsenic may reflect one mechanism underlying the role of arsenic exposure in enhancing cigarette smoke-induced lung carcinogenesis and UV light-induced skin cancer, and it may provide some insights into the emergence of arsenic trioxide as a chemotherapeutic agent.
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Holcomb
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
authors.forename: Mamta
authors.initials: M
authors.lastname: Goswami
authors.affiliation: Toxicology Laboratory, Department of Food Science and Biotechnology of Animal Resources, College of Animal Bioscience and Technology, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Sung Gu
authors.initials: SG
authors.lastname: Han
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
authors.forename: Tim
authors.initials: T
authors.lastname: Scott
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
authors.forename: John
authors.initials: J
authors.lastname: D'Orazio
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
authors.forename: David K
authors.initials: DK
authors.lastname: Orren
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States.
authors.forename: C Gary
authors.initials: CG
authors.lastname: Gairola
authors.affiliation: Department of Toxicology and Cancer Biology, The Markey Cancer Center, University of Kentucky, Lexington, KY, United States. Electronic address: mellon@uky.edu.
authors.forename: Isabel
authors.initials: I
authors.lastname: Mellon
mesh_terms: D000818:Animals; D018053:Arsenites / Q000494:pharmacology / Q000633:toxicity*; D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D007700:Kinetics; D051379:Mice; D011740:Pyrimidine Dimers / Q000378:metabolism*; D017670:Sodium Compounds / Q000494:pharmacology / Q000633:toxicity*; D014466:Ultraviolet Rays
chemical_list: D018053:Arsenites; D004268:DNA-Binding Proteins; D011740:Pyrimidine Dimers; D017670:Sodium Compounds; C086984:XPC protein, human; C059224:cyclobutyldithymidine dimers; C017947:sodium arsenite; D004247:DNA
keywords: Arsenic; Lung cancer; Nucleotide excision repair; Skin cancer; UV light; XPC