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Molecules 2017, 22(2), 194; doi:10.3390/molecules22020194

Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer

1
Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA
2
Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA
3
Department of Biological Sciences and Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA
4
Department of Urology, College of Medicine, and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
5
Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang 110122, China
*
Author to whom correspondence should be addressed.
Academic Editor: Santosh K. Katiyar
Received: 14 December 2016 / Revised: 17 January 2017 / Accepted: 20 January 2017 / Published: 24 January 2017
(This article belongs to the Special Issue Cancer Chemoprevention)
View Full-Text   |   Download PDF [1438 KB, uploaded 25 January 2017]   |  

Abstract

Exposure to inorganic arsenic in contaminated drinking water poses an environmental public health threat for hundreds of millions of people in the US and around the world. Arsenic is a known carcinogen for skin cancer. However, the mechanism by which arsenic induces skin cancer remains poorly understood. Here, we have shown that arsenic induces p62 expression in an autophagy-independent manner in human HaCaT keratinocytes. In mouse skin, chronic arsenic exposure through drinking water increases p62 protein levels in the epidermis. Nrf2 is required for basal and arsenic-induced p62 up-regulation. p62 knockdown reduces arsenic-induced Nrf2 activity, and induces sustained p21 up-regulation. p62 induction is associated with increased proliferation in mouse epidermis. p62 knockdown had little effect on arsenic-induced apoptosis, while it decreased cell proliferation following arsenic treatment. Our findings indicate that arsenic induces p62 expression to regulate the Nrf2 pathway in human keratinocytes and suggest that targeting p62 may help prevent arsenic-induced skin cancer. View Full-Text
Keywords: arsenic; p62; Nrf2; keratinocytes; apoptosis; proliferation arsenic; p62; Nrf2; keratinocytes; apoptosis; proliferation
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MDPI and ACS Style

Shah, P.; Trinh, E.; Qiang, L.; Xie, L.; Hu, W.-Y.; Prins, G.S.; Pi, J.; He, Y.-Y. Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer. Molecules 2017, 22, 194.

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