title: Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response.
abstract: Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100nM, 30weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100nM) did not induce ODD during the 30weeks required for malignant transformation. Although acute UV-treatment (UVA, 25J/cm(2)) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (>50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD.
authors.affiliation: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, and National Toxicology Laboratories, National Toxicology Program, the National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Chikara
authors.initials: C
authors.lastname: Kojima
authors.forename: Colin
authors.initials: C
authors.lastname: Chignell
authors.forename: Ronald
authors.initials: R
authors.lastname: Mason
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018053:Arsenites / Q000494:pharmacology / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D016877:Oxidants / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D018053:Arsenites; D016877:Oxidants; C015001:arsenite