Abstract
Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Due to the chemical similarity between trivalent inorganic arsenic (arsenite) and antimony (antimonite), we hypothesized that common intracellular targets lead to similarities in cellular responses. Indeed, transcriptional and proteomic profiling revealed remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite and antimonite in contrast to comparisons of arsenite with other metal compounds. These data were analyzed to predict upstream regulators and affected signaling pathways following arsenite and antimonite treatments. A majority of the top findings in each category were identical after treatment with either compound. Inspection of the predicted upstream regulators led to previously unsuspected roles for oncostatin M, corticosteroids and ephrins in mediating cellular response. The influence of these predicted mediators was then experimentally verified. Together with predictions of transcription factor effects more generally, the analysis has led to model signaling networks largely accounting for arsenite and antimonite action. The striking parallels between responses to arsenite and antimonite indicate the skin carcinogenic risk of exposure to antimonite merits close scrutiny.
Highlights
Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis
Www.nature.com/scientificreports and transcriptional profiling experiments using spontaneously immortalized human epidermal keratinocytes (SIK) demonstrated that changes due to treatment with these two agents occur in parallel[14]
FOS and JUN have been identified as transcription factors important for expression of several keratinocyte differentiation markers, reviewed in[54]
Summary
Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Transcriptional and proteomic profiling revealed remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite and antimonite in contrast to comparisons of arsenite with other metal compounds. These data were analyzed to predict upstream regulators and affected signaling pathways following arsenite and antimonite treatments. The initial targets and mechanisms of action, and how similar these are for arsenite and antimonite, remain to be determined For this purpose, we have analyzed profiling data to predict cell signaling pathways and transcription factors that appear to mediate downstream effects. Three previously unsuspected signaling pathways for these metalloids have been revealed and validated in keratinocytes, and model signaling networks largely accounting for arsenite and antimonite action are presented
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