TY - JOUR
T1 - Caffeic acid directly targets ERK1/2 to attenuate solar UV-induced skin carcinogenesis
AU - Yang, Ge
AU - Fu, Yang
AU - Malakhova, Margarita
AU - Kurinov, Igor
AU - Zhu, Feng
AU - Yao, Ke
AU - Li, Haitao
AU - Chen, Hanyong
AU - Li, Wei
AU - Lim, Do Young
AU - Sheng, Yuqiao
AU - Bode, Ann M.
AU - Dong, Ziming
AU - Dong, Zigang
N1 - Publisher Copyright:
©2014 American Association for Cancer Research.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1940-6207.CAPR-14-0141
DO - 10.1158/1940-6207.CAPR-14-0141
M3 - Article
C2 - 25104643
AN - SCOPUS:84907519021
SN - 1940-6207
VL - 7
SP - 1056
EP - 1066
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 10
ER -
