Arsenic (As) exposure through drinking water is a major public health problem. 100 million humans globally are exposed to As contaminated water. As exposure is associated with an enhanced risk for the development of various cancers including skin cancers. In human skin, As induces precancerous lesions, melenosis and keratosis some of which progress to basal cell (BCC) and squamous cell carcinoma. However, the mechanism by which these pathophysiological alterations occur remains elusive. In this study, we show that chronic As (sodium arsenite) exposure to SKH-1 mice leads to induction of unfolded protein response (UPR) signaling. UPR signaling is controlled by multiple pathways regulated by the proteins, inositol-requiring enzyme-1 (IRE-1), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6). As activated all three UPR regulatory proteins in the skin. It induced phosphorylation of cutaneous IRE-1, resulting in an augmented splicing of X-box binding protein-1 (XBP-1), which then migrated to the nucleus and activated transcription of its target proteins. Similarly, it induced hyperphosphorylation of PERK which is required to induce eukaryotic translation initial factor 2 α (eIF2α) in a phosphorylation-dependent manner.

Hyperphosphorylated eIF2α enhanced translation of ATF4. In addition, As augmented proteolytic activation of ATF6. XBP1, ATF4 and ATF6 regulate overlapping downstream target proteins including GRP94 and GRP78 chaperones. As also mediated the production of Th-1/Th-2 types of inflammatory cytokines, chemokines and receptors in skin. Consistent with these results, As treatment was associated with the enhanced expression of inflammation-associated epidermal MAP kinase signaling. Enhanced levels of p-ERK, p-p38 and p-MAPKAPK2 were observed in As-treated groups as compared to age-matched controls. In addition, we observed a disruption in iron metabolism characterized by the enhancement in hepcidin and ferroportin. This also leads to enhanced production of reactive oxygen species in the skin. Chronic As exposure to Ptch+/−/SKH-1 mice enhanced the growth of BCCs by enhancing sonic hedgehog signaling. An enhanced number of both visible and microscopic BCCs was noted in these animals. We also observed that p53 status determines the tumor-growth-related effects of As in these mice. The tumor growth enhancing effects of As were not observed in Ptch+/−/p53+/−/SKH-1. These animals showed that diminution in p53 gene dose level inhibited tumorigenesis. Our data suggest that As-mediated enhancement in UPR signaling pathways in murine skin underlie the pathogenesis of inflammation and tumor development. However, these effects are dependent on p53 mutational status.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-429. doi:10.1158/1538-7445.AM2011-LB-429