α-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes
α-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes
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DOI：
10.1158/0008-5472.can-04-4535
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发表时间：
2005-05-15
期刊：
影响因子：
11.2
通讯作者：
Abdel-Malek, ZA
中科院分区：
文献类型：
--
作者：
Kadekaro, AL;Kavanagh, R;Abdel-Malek, ZA
紫外线辐射是皮肤癌，包括黑色素瘤的重要病因。组成性色素沉着和晒黑的能力被认为是对抗阳光诱导的致癌作用的主要光保护机制。皮肤中的色素沉着由表皮黑素细胞赋予，表皮黑素细胞合成黑素并将其转移到角质形成细胞。因此，确保表皮黑素细胞的存活和基因组稳定性对于抑制光致癌作用，特别是黑色素瘤（最致命的皮肤癌形式）至关重要。旁分泌因子α-黑皮质素和内皮素-1对于培养的人黑素细胞对紫外线辐射的黑素生成反应是至关重要的。我们报告说，α-黑皮质素和内皮素-1拯救人类黑素细胞从紫外线辐射诱导的细胞凋亡和减少DNA光产物和氧化应激。α-黑皮质素和内皮素-1的存活效应分别通过黑皮质素1和内皮素受体的激活来介导。在暴露于紫外线辐射之前用α-黑皮质素和/或内皮素-1处理黑素细胞激活了三磷酸肌醇激酶-Akt通路，并增加了小眼症相关转录因子的磷酸化和表达。用α-黑皮质素和/或内皮素-1治疗增强了环丁烷嘧啶二聚体的修复，并降低了紫外线辐射诱导的过氧化氢水平。预期这些作用将减少基因组不稳定性和诱变。
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.