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cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT-mediated activation of protective responses to oxidative DNA damage

Oncogene volume 37, pages 3631–3646 (2018)Cite this article

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Abstract

The melanocortin 1 receptor gene (MC1R), a well-established melanoma susceptibility gene, regulates the amount and type of melanin pigments formed within epidermal melanocytes. MC1R variants associated with increased melanoma risk promote the production of photosensitizing pheomelanins as opposed to photoprotective eumelanins. Wild-type (WT) MC1R activates DNA repair and antioxidant defenses in a cAMP-dependent fashion. Since melanoma-associated MC1R variants are hypomorphic in cAMP signaling, these non-pigmentary actions are thought to be defective in MC1R-variant human melanoma cells and epidermal melanocytes, consistent with a higher mutation load in MC1R-variant melanomas. We compared induction of antioxidant enzymes and DNA damage responses in melanocytic cells of defined MC1R genotype. Increased expression of catalase (CAT) and superoxide dismutase (SOD) genes following MC1R activation was cAMP-dependent and required a WT MC1R genotype. Conversely, pretreatment of melanocytic cells with an MC1R agonist before an oxidative challenge with Luperox decreased (i) accumulation of 8-oxo-7,8-dihydro-2′-deoxyguanine, a major product of oxidative DNA damage, (ii) phosphorylation of histone H2AX, a marker of DNA double-strand breaks, and (iii) formation of DNA breaks. These responses were comparable in cells WT for MC1R or harboring hypomorphic MC1R variants without detectable cAMP signaling. In MC1R-variant melanocytic cells, the DNA-protective responses were mediated by AKT. Conversely, in MC1R-WT melanocytic cells, high cAMP production downstream of MC1R blocked AKT activation and was responsible for inducing DNA repair. Accordingly, MC1R activation could promote repair of oxidative DNA damage by a cAMP-dependent pathway downstream of WT receptor, or via AKT in cells of variant MC1R genotype.

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Acknowledgements

Supported by grants SAF2015-67092-R from MINECO (Spain) and FEDER (European Community) and 19875/GERM/15 from Fundación Seneca, Comunidad Autónoma de la Región de Murcia (CARM). M Castejón holds a pre-doctoral fellowship from the Fundación Seneca. Cecilia Herraiz was a Juan de la Cierva-Incorporación fellow of MINECO. We thank Prof. G Ghanem, from the Free University of Brussels for gift of human melanoma cell lines and Prof. Neptuno Rodríguez (University of Murcia) for Hermes melanocytes. We also thank Prof. JL Castejón for help with the statistical analysis of data, Dr. M Abrisqueta for assistance in cell cycle analysis and Dr. A López-Contreras for suggestions and critical reading of the manuscript.

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  1. Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain

    María Castejón-Griñán, Cecilia Herraiz, Conchi Olivares, Celia Jiménez-Cervantes & Jose Carlos García-Borrón

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  1. María Castejón-Griñán
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Castejón-Griñán, M., Herraiz, C., Olivares, C. et al. cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT-mediated activation of protective responses to oxidative DNA damage. Oncogene 37, 3631–3646 (2018). https://doi.org/10.1038/s41388-018-0216-1

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