Mechanisms of arsenic toxicity and carcinogenesis in UVR-induced human skin cancer.

摘要

Inorganic arsenic has been classified as a known human carcinogen based on strong epidemiological data and is associated with human skin cancer. Skin cancer is a disease that occurs frequently in light-skinned populations and, indeed, the incidence of new skin cancer cases each year in the USA is currently estimated to be between 900,000-1,200,000, roughly equivalent to the annual incidence of all other malignancies combined.; The induction of oxidative stress is proposed as one possible carcinogenic mechanism of arsenic. In the current study, our data demonstrated that inorganic arsenic compounds induced oxidative stress to both DNA and protein in HaCat cells. Furthermore, we demonstrated the first time that peroxynitrite (ONOO -) played a key role in arsenic induced oxidative stress.; Strong evidences prove that environmentally relevant concentrations of As(III) acts as a co-carcinogen in UVR-induced skin cancer in mice skin. To investigate whether this hypothesis was also true in human was another goal of current research. In the current study, using HaCat cells as the in vitro model, we demonstrated that environmentally relevant concentrations of As(III) interfered with repair of UVR-induced oxidative DNA damage, using 8-hydroxyl-2'-deoxyguanosine (8-OHdG) as the biomarker. Our data provided important evidences for a potential mechanism involved in the co-carcinogenic activities of As(III) in UVR-induced human skin cancer, and inhibition of PARP-1 activity might represent a molecular target for As(III)-dependent disruption of DNA repair.; Cyclobutane pyrimidine dimers (CPDs), a major photoproduct induced by UVR, are major causes of mutations identified in non-melanoma skin cancers. Our data demonstrated that low concentrations of As(III) inhibited UVR-induced CPD damage repair after exposing cells to low doses of UVR in a concentration-dependent manner. Further evidences showed that Zn(II) counteracted the inhibition effect of As(III) on UVR-induced CPDs repair, which implicated that one or more zinc-finger protein(s) was affected by As(III) during the process of CPDs repair. Our data provide the first direct evidence of As(III) inhibition of UV-induced CPDs repair in human keratinocytes and the underlying molecular mechanism may involved the inhibition of zinc-finger protein(s) during CPDs repair process.