title: Caffeic acid directly targets ERK1/2 to attenuate solar UV-induced skin carcinogenesis.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ge
authors.initials: G
authors.lastname: Yang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota. The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Margarita
authors.initials: M
authors.lastname: Malakhova
authors.affiliation: Cornell University, NE-CAT, APS, Argonne, Illinois.
authors.forename: Igor
authors.initials: I
authors.lastname: Kurinov
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.affiliation: 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.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Physiology and Pathophysiology, Basic Medical College, Zhengzhou University, ZhengZhou, China. zgdong@hi.umn.edu Dongzm@zzu.edu.cn.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota. zgdong@hi.umn.edu Dongzm@zzu.edu.cn.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001667:Binding, Competitive; D002109:Caffeic Acids / Q000737:chemistry*; D063646:Carcinogenesis; D003460:Crystallization; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009381:Neoplasms, Radiation-Induced / Q000517:prevention & control; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D012878:Skin Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D002109:Caffeic Acids; D011994:Recombinant Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C040048:caffeic acid
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