title: alpha-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 alpha-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that alpha-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of alpha-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with alpha-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 alpha-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.
authors.affiliation: Department of Dermatology, University of Cincinnati College of Medicine and Shriners' Burns Institute, Cincinnati, Ohio 45267-0592, USA.
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Kadekaro
authors.forename: Renny
authors.initials: R
authors.lastname: Kavanagh
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kanto
authors.forename: Silva
authors.initials: S
authors.lastname: Terzieva
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hauser
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Sandy
authors.initials: S
authors.lastname: Schwemberger
authors.forename: James
authors.initials: J
authors.lastname: Cornelius
authors.forename: George
authors.initials: G
authors.lastname: Babcock
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Glynis
authors.initials: G
authors.lastname: Scott
authors.forename: Zalfa A
authors.initials: ZA
authors.lastname: Abdel-Malek
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D051739:Microphthalmia-Associated Transcription Factor; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D019332:Endothelin-1; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D000521:alpha-MSH; D004247:DNA; D006861:Hydrogen Peroxide; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt