Prevention of solar UV-induced skin cancer by targeting LTA4H

 描述(申请人提供)：皮肤癌是最常见的人类癌症，也是美国发病率最高的癌症。太阳光中的紫外线辐射 在皮肤中引起各种生物反应，包括炎症、色素沉着、红斑和细胞死亡，因此紫外线作为主要致病因素的作用特别值得关注。使用防晒霜或防晒霜在预防皮肤癌方面并不有效，因此迫切需要新的基于机制的方法来治疗紫外线诱导的皮肤癌。本项目旨在研究白三烯A4水解酶(LTA4H)在太阳紫外线(UV)诱导的皮肤癌变中的作用。LTA4H被证明在某些类型的癌症中显示出高水平的蛋白表达，并且它的抑制导致在各种动物模型中癌症发病率的降低。重要的是，我们的初步数据表明，在7，12-二甲基苯并[a]菲(DMBA)/12-O-十四酰佛波醇-13-醋酸酯(TPA)两阶段小鼠皮肤癌变模型中，抑制LTA4H的表达和活性可以减少皮肤癌的发生。我们还报道了[6]-姜辣素或白藜芦醇分别与LTA4H结合，在体内抑制结肠癌或胰腺癌细胞的生长。我们假设，[6]-姜酚或白藜芦醇抑制LTA4H将导致抑制太阳紫外线诱导的皮肤癌发生。

 DESCRIPTION (provided by applicant): Skin cancer is the most common human cancer and the number one cancer in terms of incidence in the USA. Ultraviolet (UV) irradiation in solar light elicits various biological responses in the skin, including inflammation, pigmentation, erythema, and cell death, and therefore the role of UV light as a major etiologic factor is of particular concern. The use of sunscreens or sun blocks has not been effective in preventing skin cancer, and therefore new mechanism-based approaches are critically needed to treat UV-induced skin cancer. This project is aimed toward investigating the role of leukotriene A4 hydrolase (LTA4H) in solar ultraviolet (UV) - induced skin carcinogenesis. LTA4H was shown to exhibit high levels of protein expression in certain types of cancers and its inhibition leads to a reduced cancer incidence in various animal models. Importantly, our preliminary data indicate that suppressing LTA4H expression and activity decreases skin carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage mouse skin carcinogenesis model. We also reported that [6]-gingerol or resveratrol binds with LTA4H to suppress colon or pancreatic cancer cell growth, respectively, in vivo. We hypothesize that inhibition of LTA4H by [6]-gingerol or resveratrol will result in suppression of solar UV-induced skin carcinogenesis.