Carcinogenesis Advance Access published online on December 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn282
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Caffeic Acid, a Phenolic Phytochemical in Coffee, directly inhibits Fyn Kinase Activity and UVB-induced COX-2 Expression
1 Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin MN, USA
2 Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-742, Republic of Korea
3 Departments of Bioscience and Biotechnology
4 Chemistry, Konkuk University, Seoul 143-701, Republic of Korea
* To whom correspondence should be addressed at: Zigang Dong, Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota 55912, Tel.: +1-507-437-9600; Fax: +1-507-437-9606; E-mail: zgdong{at}hi.umn.edu. Hyong Joo Lee, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea. Tel.: +82-2-880-4860; Fax: +82-2-873-5095; E-mail: leehyjo{at}snu.ac.kr
Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in many foods, including coffee. Recent studies suggested that caffeic acid exerts anticarcinogenic effects, but little is known about the underlying molecular mechanisms and specific target proteins. In this study, we found that Fyn, one of the members of the nonreceptor protein tyrosine kinase family, was required for UVB-induced COX-2 expression, and caffeic acid suppressed UVB-induced skin carcinogenesis by directly inhibiting Fyn kinase activity. Caffeic acid more effectively suppressed UVB-induced COX-2 expression and subsequent prostaglandin E2 (PGE2) production in JB6 P+ mouse skin epidermal (JB6 P+) cells compared to chlorogenic acid (5-O-cafeoylquinic acid), an ester of caffeic acid with quinic acid. Data also revealed that caffeic acid more effectively induced the down-regulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein (AP)-1 and nuclear factor (NF)-
B transcription activity compared to chlorogenic acid. Fyn kinase activity was suppressed more effectively by caffeic acid than by chlorogenic acid, and downstream mitogen-activated protein (MAP) kinases were subsequently blocked. Pharmacological Fyn kinase inhibitor (PP2 and leflunomide) data also revealed that Fyn is involved in UVB-induced COX-2 expression mediated through the phosphorylation of MAP kinases in JB6 P+ cells. Pull-down assays revealed that caffeic acid directly bound with Fyn and noncompetitively with ATP. In vivo data from mouse skin also supported the idea that caffeic acid suppressed UVB-induced COX-2 expression by blocking Fyn kinase activity. These results suggested that this compound could act as a potent chemopreventive against skin cancer.
Key Words: Caffeic acid • cyclooxygenase-2 • Fyn
5 These authors contributed equally to this work.
Received September 20, 2008; revised December 1, 2008; accepted December 3, 2008.