期刊
CANCER PREVENTION RESEARCH
卷 7, 期 10, 页码 1056-1066出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1940-6207.CAPR-14-0141
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资金
- National Institute of General Medical Sciences from the NIH [P41 GM103403]
- U.S. DOE [DE-AC02-06CH11357]
- Hormel Foundation
- National Institutes of Health [R37 CA081064, CA166011, CA172457, ES016548]
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. (C) 2014 AACR.
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