Alpha-Melanocyte–Stimulating Hormone Suppresses Oxidative Stress through a p53-Mediated Signaling Pathway in Human Melanocytes

Abstract

Epidermal melanocytes are skin cells specialized in melanin production. Activation of the melanocortin 1 receptor (MC1R) on melanocytes by a-melanocyte-stimulating hormone (a-MSH) induces synthesis of the brown/black pigment eumelanin that confers photoprotection from solar UV radiation (UVR). Contrary to keratinocytes, melanocytes are slow proliferating cells that persist in the skin for decades, in an environment with high levels of UVR-induced reactive oxygen species (ROS). We previously reported that in addition to its role in pigmentation, a-MSH also reduces oxidative stress and enhances the repair of DNA photoproducts in melanocytes, independent of melanin synthesis. Given the significance of ROS in carcinogenesis, here we investigated the mechanisms by which a-MSH exerts antioxidant effects in melanocytes. We show that activation of the MC1R by a-MSH contributes to phosphorylation of p53 on serine 15, a known requirement for stabilization and activation of p53, a major sensor of DNA damage. This effect is mediated by the cAMP/PKA pathway and by the activation of phosphoinositide 3-kinase (PI3K) ATR and DNA protein kinase (DNA-PK). a-MSH increases the levels of 8-oxoguanine DNA glycosylase (OGG1) and apurinic apyrimidinic endonuclease 1 (APE-1/Ref-1), enzymes essential for base excision repair. Nutlin-3, an HDM2 inhibitor, mimicked the effects of a-MSH resulting in reduced phosphorylation of H2AX (g-H2AX), a marker of DNA damage. Conversely, the p53 inhibitor pifithrin-a or silencing of p53 abolished the effects of a-MSH and augmented oxidative stress. These results show that p53 is an important target of the downstream MC1R signaling that reduces oxidative stress and possibly malignant transformation of melanocytes. Mol Cancer Res; 10(6); 778-86. Ó2012 AACR. IntroductionThe melanocortin 1 receptor (MC1R) is best known for its role in stimulating eumelanin synthesis in melanocytes (MC). In the skin, presence of eumelanin is considered the major photoprotective factor against UV radiation (UVR)-induced DNA damage and carcinogenesis. Eumelanin creates not only a physical barrier against the deep penetration of UVR into the epidermal and dermal layers (1) but also reduces oxidative stress by scavenging free radicals (2-4).

The Efficacy of Afamelanotide and Narrowband UV-B Phototherapy for Repigmentation of Vitiligo

“…26 The potential therapeutic efficacy may be further enhanced by the ability of afamelanotide to scavenge reactive oxygen species. 27 Further studies are indeed necessary to elucidate whether afamelanotide combined with NB-UV-B or as monotherapy can be used to potentially reverse pathogenic mechanisms in patients with vitiligo.…”

Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms

“…The protective tanning response of UV-irradiated skin is largely dependent on paracrine production of MC1R agonists (Cui et al, 2007) and induction of MC1R expression in melanocytes (Corre et al, 2006). MC1R activation stimulates melanogenic enzymatic activities within melanocytes (Ito and Wakamatsu, 2011;Le Pape et al, 2008) and also triggers DNA repair mechanisms (Böhm et al, 2005;Kadekaro et al, 2005;Kadekaro et al, 2010) and antioxidant defenses (Kadekaro et al, 2012;Maresca et al, 2010) that act coordinately to limit the cytotoxicity and carcinogenic potential of UVR. Thus, carriers of hypomorphic MC1R variants normally display an inefficient or absent tanning response (Healy et al, 2000;Rees, 2004) and a higher risk of melanoma and non-melanoma skin cancer (Box et al, 1997;Box et al, 2001;Duffy et al, 2004;Duffy et al, 2010;Palmer et al, 2000).…”

“…High MC1R activity is associated with eumelanogenesis and darker pigmentation (Ito and Wakamatsu, 2011;Rees, 2004;Robbins et al, 1993), whereas decreased or absent signaling leads to reddish pheomelanogenic pigment production (Beaumont et al, 2007;Duffy et al, 2004;Healy et al, 2000;Healy et al, 2001;Jiménez-Cervantes et al, 2001;Sánchez-Laorden et al, 2006;Walker and Gunn, 2010). Following exposure to ultraviolet radiation (UVR), MC1R also activates DNA repair and survival mechanisms (Böhm et al, 2005;Kadekaro et al, 2005;Kadekaro et al, 2010) as well as antioxidant defences (Kadekaro et al, 2012;Maresca et al, 2010). In human melanocytes, the low density of MC1R receptors on the plasma membrane is a limiting factor for the cAMP response to agonists (Herraiz et al, 2011b;Más et al, 2003).…”

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer’s Disease Risk

“…The MC1R activation has anti-inflammatory and immunomodulatory effects in brain cells [16] and promotes pigmentation synthesis in melanocytes [17]. It has been established that several MC1R polymorphisms constitute a risk factor to develop skin cancer (melanoma and non-melanoma skin cancer) [18,19], in part, by promoting an increased oxidative stress in skin cells [20]. Notably, co-occurrence of Parkinson's disease (PD) and cutaneous melanoma (CM) has been reported in epidemiological studies [21] and previous evidence indicates that MC1R is involved in the bidirectional link between both diseases [22,23].…”