Arsenic leads to autophagy of keratinocytes by increasing aquaporin 3 expression

Sebastian Yu,Palaniraja Jeyakannu,Jeh-Jeng Wang,Ling-Hau Li,Chih-Hung Lee,Chien-Hui Hong

doi:10.1038/s41598-021-96822-6

Abstract

Exposure to arsenic, a ubiquitous metalloid on Earth, results in human cancers. Skin cancer is the most common arsenical cancers. Both autophagy and aquaporin pathway are known to promote carcinogenesis. However, the mechanisms by which arsenic regulates aquaporin and autophagy in arsenical skin cancers remain elusive. This study aims to address how arsenic regulates aquaporin-3, the predominant aquaporin in epidermal keratinocytes, and how this process would induce autophagy. Quantitative real-time PCR and immunofluorescence were used to measure the expression of aquaporin 3 in arsenical skin cancers and arsenic-treated keratinocytes. Beclin-1 expression and autophagy were measured. We examined if blocking aquaporin 3 could interfere arsenic-induced autophagy in keratinocytes. Expression of aquaporin 3 is increased in arsenical cancers and in arsenic-treated keratinocytes. Arsenic induced autophagy in primary human keratinocytes. Notably, the arsenic-induced autophagy was inhibited by pretreatment of keratinocytes with aquaporin inhibitors Auphen or AgNO3, or RNA interference against aquaporin 3. The data indicates that the aquaporin 3 is an important cell membrane channel to mediate arsenic uptake and contributes to the arsenic-induced autophagy.

Highlights

Exposure to arsenic, a ubiquitous metalloid on Earth, results in human cancers
Because aquaporin 3 (AQP3) may facilitate arsenic absorption into keratinocytes, we asked whether AQP3 was increased in As-Bowen’s disease (BD) skin lesions (Fig. 1)
We further examined if increased AQP3 expression could be reproduced in protein level

Summary

Introduction

A ubiquitous metalloid on Earth, results in human cancers. Skin cancer is the most common arsenical cancers. Dysregulation of calcium homeostasis that leads to abnormal keratinocyte differentiation is one of the mechanisms underlying arsenic-induced carcinogenesis. The STAT3-VEGF axis in keratinocytes inhibits DC migration in the microenvironment of As-BD and explains why the DC migration is impaired in arsenical cancers[9] Another mechanism underlying As-BD is mitochondrial b iogenesis[10,11]. In an skin-equivalent organotypic culture model consisting of keratinocytes, fibroblasts, and peripheral blood mononuclear cells, arsenic treatment leads to pathognomonic characteristics of As-BD. By using this model, we identified arsenic induces epigenetic modification of E2F1 promotor, which leads to centromere amplification and subsequent caspase-8-mediated apoptosis of keratinocytes[12]

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