Arsenite and antimonite signaling pathways

Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Human carcinogenicity of oxides of the chemically related element, antimony, is less certain. Transcriptional and proteomic profiling reveal remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite (AsIII) and antimonite (SbIII). These data were analyzed to predict downstream effects, upstream regulators and affected signaling pathways. A majority of the top findings in each category were identical after treatment with either compound. Top predicted downstream effects included categories related to cell injury, growth, survival and cancer. A major canonical pathway predicted to be affected by both arsenite and antimonite is the Nrf2-mediated oxidative stress response, while top predicted upstream regulators included oncostatin M, dexamethasone (a synthetic corticosteroid), NFE2L2 (Nrf2) and arsenite. Experimental evidence showed that oncostatin M and corticosteroids elicited several of the same transcriptional responses observed after arsenite and antimonite treatments. The striking parallels between responses to arsenite and antimonite indicate the skin carcinogenic risk of exposure to antimonite merits closer scrutiny.

无机砷氧化物已被证实可诱发包括表皮在内的多种人体组织癌变。而化学性质相近的锑氧化物对人体的致癌性则尚未明确。通过转录组学（Transcriptional profiling）与蛋白质组学（proteomic profiling）分析发现，在培养的人表皮角质形成细胞分别暴露于亚砷酸盐（AsIII，三价砷）与亚锑酸盐（SbIII，三价锑）后，二者诱导的差异表达基因与蛋白质存在显著相似性。本研究对上述数据进行分析，以预测两种暴露后的下游效应、上游调控因子及受影响的信号通路。两类化合物处理后，各分类中的多数核心结果均保持一致。预测得到的核心下游效应涵盖细胞损伤、细胞增殖、存活及癌变相关类别。预测得到的受两种化合物共同影响的核心经典信号通路为Nrf2介导的氧化应激应答，而核心上游调控因子则包括抑瘤素M（oncostatin M）、地塞米松（dexamethasone，一种合成糖皮质激素）、NFE2L2（Nrf2）及亚砷酸盐。实验证据表明，抑瘤素M与糖皮质激素可诱导出与亚砷酸盐、亚锑酸盐处理后相似的多种转录应答反应。亚砷酸盐与亚锑酸盐暴露后的应答存在显著相似性，这提示暴露于亚锑酸盐所带来的皮肤致癌风险值得进一步深入研究。