α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes

Abstract

UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors A-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that A-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of A-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with A-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with A-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis. (Cancer Res 2005; 65(10): 4292-9)

MC1R variants associated susceptibility to basal cell carcinoma of skin: Interaction with host factors and XRCC3 polymorphism

“…38 The synthesis of melanocortins in skin is reported to enhance DNA repair, preserve melanocyte survival and stimulate melanogenesis to provide optimal photoprotection mediated via MC1R. 2,39,40 One of the plausible explanations for the effect on a tumor of keratinocytes by MC1R expressed primarily in melanocytes could be due to reduced protection from UV induced DNA damage because of perturbed eumelanin/phaeomelanin balance. Melanin produced in melanosomes inside melanocytes is delivered to keratinocytes.…”

A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions

“…The far lower observed mean mole count probably reflects the usually high efficiency of DNA damage surveillance and repair, essential in melanocytes given their role in photoprotection and known resistance to apoptotic signals following UV exposure. 30 Environmental exposures that affect the somatic mutation rate (such as UV exposure) and genetic variation in known and yet to be characterised tumour suppressor genes will explain both interindividual difference and the considerable familial correlations in mole count.…”

Melanocytes and Oxidative Stress

“…As key players in the homeostasis of epidermal cells, in particular melanocytes, paracrine factors are influencing the redox status of the latter. Endothelin-1 (ET-1) produced by the keratinocytes is a melanogenic factor reducing H 2 O 2 generation in melanocytes [27]. ACTH, which is further processed by amidation and acetylation to α-MSH, has been identified in both melanocytes and keratinocytes [28].…”

“…Most of the actions of α-MSH in the skin are via the melacortin-1 receptor (MC-1R) expressed on the cell surface of melanocytes. α-MSH stimulation increases both levels and activity of catalase and reduces UV-induced H 2 O 2 expression [27,29] reducing oxidative DNA damage induced by the same [23]. Further, activation of MC-1R by α-MSH regulates intracellular redox status by up regulating the expression of various antioxidant genes (heme oxygenase-1 [HO-1], ferritin and peroxiredoxin-1) [23,30], Mitf, and APE-1 [27].…”