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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Melanomas and the melanocytes from which they arise are subject to the damaging effects of reactive oxygen species (ROS) from exogenous and endogenous sources. Many attempts have been made to counteract these effects with antioxidant drugs and natural products. Here, we demonstrate that the antioxidant enzyme thioredoxin reductase-1 controls the stability and function of MITF, the master regulator of melanocytes and melanoma. We believe that understanding these phenomena will generate new melanoma treatment and prevention strategies that are far more effective than brute-force approaches that attempt to simply eliminate ROS from vulnerable tissues and tumors.

Abstract

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in oxidation of MITF itself. This newly discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage.

Details

Title
MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1
Author
Kline, Chelsey D 1 ; Anderson, Madeleine 1 ; Bassett, John W 1 ; Kent, Gail 1 ; Berryman, Rachel 1 ; Honeggar, Matthew 1 ; Ito, Shosuke 2   VIAFID ORCID Logo  ; Wakamatsu, Kazumasa 2   VIAFID ORCID Logo  ; Indra, Arup K 3   VIAFID ORCID Logo  ; Moos, Philip J 4 ; Leachman, Sancy A 5 ; Cassidy, Pamela B 5   VIAFID ORCID Logo 

 Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA 
 Institute for Melanin Chemistry, Fujita Health University, Toyoake 470-1192, Japan 
 Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA; Department of Dermatology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA 
 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA 
 Department of Dermatology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA 
First page
5011
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2728448420
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.