Yang Ge, Fu Yang, Malakhova Margarita, Kurinov Igor, Zhu Feng, Yao Ke, Li Haitao, Chen Hanyong, Li Wei, Lim Do Young, Sheng Yuqiao, Bode Ann M, Dong Ziming, Dong Zigang
The Hormel Institute, University of Minnesota, Austin, Minnesota. Physiology and Pathophysiology, Basic Medical College, Zhengzhou University, ZhengZhou, China. The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China.
The Hormel Institute, University of Minnesota, Austin, Minnesota. The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China.
Cancer Prev Res (Phila). 2014 Oct;7(10):1056-66. doi: 10.1158/1940-6207.CAPR-14-0141. Epub 2014 Aug 7.
Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in coffee and reportedly has anticancer activities. However, the underlying molecular mechanisms and targeted proteins involved in the suppression of carcinogenesis by caffeic acid are not fully understood. In this study, we report that caffeic acid significantly inhibits colony formation of human skin cancer cells and EGF-induced neoplastic transformation of HaCaT cells dose-dependently. Caffeic acid topically applied to dorsal mouse skin significantly suppressed tumor incidence and volume in a solar UV (SUV)-induced skin carcinogenesis mouse model. A substantial reduction of phosphorylation in mitogen-activated protein kinase signaling was observed in mice treated with caffeic acid either before or after SUV exposure. Caffeic acid directly interacted with ERK1/2 and inhibited ERK1/2 activities in vitro. Importantly, we resolved the cocrystal structure of ERK2 complexed with caffeic acid. Caffeic acid interacted directly with ERK2 at amino acid residues Q105, D106, and M108. Moreover, A431 cells expressing knockdown of ERK2 lost sensitivity to caffeic acid in a skin cancer xenograft mouse model. Taken together, our results suggest that caffeic acid exerts chemopreventive activity against SUV-induced skin carcinogenesis by targeting ERK1 and 2.
咖啡酸（3,4 - 二羟基肉桂酸）是一种存在于咖啡中的著名酚类植物化学物质，据报道具有抗癌活性。然而，咖啡酸抑制致癌作用所涉及的潜在分子机制和靶向蛋白尚未完全明确。在本研究中，我们报告咖啡酸能显著剂量依赖性地抑制人皮肤癌细胞的集落形成以及表皮生长因子（EGF）诱导的HaCaT细胞的肿瘤转化。局部涂抹于小鼠背部皮肤的咖啡酸在紫外线（SUV）诱导的皮肤癌发生小鼠模型中显著抑制了肿瘤发生率和肿瘤体积。在用咖啡酸处理的小鼠中，无论在SUV暴露之前还是之后，均观察到丝裂原活化蛋白激酶信号通路中的磷酸化显著减少。咖啡酸在体外直接与细胞外信号调节激酶1/2（ERK1/2）相互作用并抑制其活性。重要的是，我们解析了与咖啡酸复合的ERK2的共晶体结构。咖啡酸在氨基酸残基Q105、D106和M108处直接与ERK2相互作用。此外，在皮肤癌异种移植小鼠模型中，表达ERK2基因敲低的A431细胞对咖啡酸失去敏感性。综上所述，我们的结果表明咖啡酸通过靶向ERK1和ERK2对SUV诱导的皮肤癌发生发挥化学预防作用。
