Low dose arsenite confers resistance to UV induced apoptosis via p53-MDM2 pathway in ketatinocytes

Y Zhou,F Li,C Peng,J Zhang,M Gao,W Zhong,J Su,M Qi,Y He,Y Duan,X Xu,X Hu,W Zeng,S Zhao,X Chen

doi:10.1038/oncsis.2017.67

Abstract

Chronic arsenite and ultraviolet (UV) exposure are associated with skin tumor. To investigate the details by low concentrations of arsenite and UV induced carcinogenesis in skin, hTERT-immortalized human keratinocytes were used as a cellular model with exposure to low concentrations of sodium arsenite and UV. The effect of NaAsO2 on UV treatment-induced apoptosis was measured by flow cytometry and Hoechst staining. We found that the cell apoptosis induced by UV exposure was significantly attenuated after exposure to low-dose arsenite, and knockdown of p53 could block UV-induced apoptosis indicating that this phenomenon depended on p53. Interestingly, the expression of murine double minute 2 (MDM2), including its protein and transcriptional levels, was remarkably high after exposure to low-dose arsenite. Moreover, low-dose arsenite treatment dramatically decreased the MDM2 gene promoter activity, suggesting that this effect has been mediated through transcription. In addition, treatment of PD98059 reversed low-dose arsenite-induced MDM2 expression, and the inhibition of ERK2 expression could significantly block MDM2 expression as a consequence, and p53 expression automatically was increased. To validate the role of p53 in exposure to low-dose arsenite, the expression of p53 was examined by immunohistochemistry in the skin of Sprague−Dawley rats model by chronic arsenite exposure for 6 months and in patients with arsenic keratosis, and the results showed that the expression of p53 was decreased in those samples. Taken together, our results demonstrated that low-dose arsenite-induced resistance to apoptosis through p53 mediated by MDM2 in keratinocytes.

Highlights

Human exposure to inorganic arsenic is unavoidable, because the metal is naturally present in food, soil, water and airborne particles, leading to widespread human exposure
Immunohistochemistry was performed to observe the expression of p53 in the skin of Sprague−Dawley (SD) rats after chronic arsenite exposure for 6 months and in patients with arsenic keratosis
Carcinogenic substances may change a cell’s propensity toward apoptosis. To determine whether this is the case with arsenic, we examined the influence of sodium arsenite on the rate of apoptosis in keratinocytes

Summary

Introduction

Human exposure to inorganic arsenic is unavoidable, because the metal is naturally present in food, soil, water and airborne particles, leading to widespread human exposure. Exposure to arsenic may lead to chromosome instability,[2,3] gene mutation/amplification/suppression,[4,5] altered DNA repair,[6,7] altered transcriptional regulation,[8] altered growth factor expression[9] and enhanced cell proliferation. All these events are related to tumorigenesis.[8,10,11] long-term exposure to inorganic arsenic has been reported to be associated with an increased risk of developing cancer in many organs, especially the skin, urinary bladder and lungs.[12,13,14] An elevated incidence of skin cancers and hyperkeratosis is associated with chronic exposure to arsenic, from drinking water.[15]

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