Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Pigment Cell Melanoma Res. 2009 Dec;22(6):809-18. doi: 10.1111/j.1755-148X.2009.00615.x. Epub 2009 Jul 29.
Exposure of cultured human melanocytes to ultraviolet radiation (UV) results in DNA damage. In melanoma, UV-signature mutations resulting from unrepaired photoproducts are rare, suggesting the possible involvement of oxidative DNA damage in melanocyte malignant transformation. Here we present data demonstrating immediate dose-dependent generation of hydrogen peroxide in UV-irradiated melanocytes, which correlated directly with a decrease in catalase activity. Pretreatment of melanocytes with alpha-melanocortin (alpha-MSH) reduced the UV-induced generation of 7,8-dihydro-8-oxyguanine (8-oxodG), a major form of oxidative DNA damage. Pretreatment with alpha-MSH also increased the protein levels of catalase and ferritin. The effect of alpha-MSH on 8-oxodG induction was mediated by activation of the melanocortin 1 receptor (MC1R), as it was absent in melanocytes expressing loss-of-function MC1R, and blocked by concomitant treatment with an analog of agouti signaling protein (ASIP), ASIP-YY. This study provides unequivocal evidence for induction of oxidative DNA damage by UV in human melanocytes and reduction of this damage by alpha-MSH. Our data unravel some mechanisms by which alpha-MSH protects melanocytes from oxidative DNA damage, which partially explain the strong association of loss-of-function MC1R with melanoma.
培养的人类黑素细胞暴露于紫外线辐射（UV）会导致 DNA 损伤。在黑色素瘤中，由于未修复的光产物导致的 UV 特征性突变很少，这表明氧化 DNA 损伤可能参与了黑素细胞恶性转化。在这里，我们提供的数据证明了在 UV 照射的黑素细胞中立即产生与剂量相关的过氧化氢，这与过氧化氢酶活性的直接下降直接相关。用 α-促黑素细胞激素（α-MSH）预处理黑素细胞可减少 UV 诱导的 7,8-二氢-8-氧鸟嘌呤（8-oxodG）的产生，8-oxodG 是氧化 DNA 损伤的主要形式。α-MSH 预处理还增加了过氧化氢酶和铁蛋白的蛋白水平。α-MSH 对 8-oxodG 诱导的作用是通过激活黑素皮质素 1 受体（MC1R）介导的，因为在表达功能丧失型 MC1R 的黑素细胞中不存在这种作用，并且同时用 agouti 信号蛋白（ASIP）的类似物 ASIP-YY 处理也会阻断这种作用。这项研究为 UV 在人类黑素细胞中诱导氧化 DNA 损伤以及 α-MSH 减少这种损伤提供了确凿的证据。我们的数据揭示了 α-MSH 保护黑素细胞免受氧化 DNA 损伤的部分机制，这部分解释了功能丧失型 MC1R 与黑色素瘤之间的强烈关联。
