Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Cancer Prev Res (Phila). 2010 Dec;3(12):1621-9. doi: 10.1158/1940-6207.CAPR-10-0137. Epub 2010 Oct 8.
Dietary grape seed proanthocyanidins (GSP) inhibit photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. As ultraviolet B (UVB)-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) has been implicated in skin cancer risk, we studied whether dietary GSPs enhance repair of UVB-induced DNA damage and, if so, what is the potential mechanism? Supplementation of GSPs (0.5%, w/w) with AIN76A control diet significantly reduced the levels of CPD(+) cells in UVB-exposed mouse skin; however, GSPs did not significantly reduce UVB-induced CPD(+) cells in the skin of interleukin-12p40 (IL-12) knockout (KO) mice, suggesting that IL-12 is required for the repair of CPDs by GSPs. Using IL-12 KO mice and their wild-type counterparts and standard photocarcinogenesis protocol, we found that supplementation of control diet with GSPs (0.5%, w/w) significantly reduced UVB-induced skin tumor development in wild-type mice, which was associated with the elevated mRNA levels of nucleotide excision repair genes, such as XPA, XPC, DDB2, and RPA1; however, this effect of GSPs was less pronounced in IL-12 KO mice. Cytostaining analysis revealed that GSPs repaired UV-induced CPD(+) cells in xeroderma pigmentosum complementation group A (XPA)-proficient fibroblasts from a healthy individual but did not repair in XPA-deficient fibroblasts from XPA patients. Furthermore, GSPs enhance nuclear translocation of XPA and enhanced its interactions with other DNA repair protein ERCC1. Together, our findings reveal that prevention of photocarcinogenesis by GSPs is mediated through enhanced DNA repair in epidermal cells by IL-12- and XPA-dependent mechanisms.
膳食葡萄籽原花青素（GSP）抑制小鼠光致癌作用；然而，这种作用的分子机制尚未完全阐明。由于紫外线 B（UVB）诱导的以环丁烷嘧啶二聚体（CPD）形式的 DNA 损伤与皮肤癌风险有关，我们研究了膳食 GSP 是否增强 UVB 诱导的 DNA 损伤的修复，如果是这样，潜在的机制是什么？在 AIN76A 对照饮食中补充 GSP（0.5%，w/w）可显著降低 UVB 暴露小鼠皮肤中 CPD(+)细胞的水平；然而，GSP 并没有显著减少白细胞介素 12p40（IL-12）敲除（KO）小鼠皮肤中 UVB 诱导的 CPD(+)细胞，表明 IL-12 是 GSP 修复 CPD 所必需的。使用 IL-12 KO 小鼠及其野生型对照和标准光致癌发生方案，我们发现对照饮食中补充 GSP（0.5%，w/w）可显著降低野生型小鼠中 UVB 诱导的皮肤肿瘤发生，这与核苷酸切除修复基因，如 XPA、XPC、DDB2 和 RPA1 的 mRNA 水平升高有关；然而，GSP 的这种作用在 IL-12 KO 小鼠中不太明显。细胞染色分析表明，GSP 修复了来自健康个体的 XPA 功能正常的成纤维细胞中 UV 诱导的 CPD(+)细胞，但不能修复来自 XPA 患者的 XPA 缺陷型成纤维细胞中的 CPD(+)细胞。此外，GSP 增强了 XPA 的核易位，并增强了其与其他 DNA 修复蛋白 ERCC1 的相互作用。总之，我们的研究结果表明，GSP 通过 IL-12 和 XPA 依赖的机制增强表皮细胞中的 DNA 修复来介导光致癌作用的预防。
