title: Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression.
abstract: 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 non-receptor protein tyrosine kinase family, was required for ultraviolet (UV) B-induced cyclooxygenase-2 (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 E(2) production in JB6 P+ mouse skin epidermal (JB6 P+) cells compared with chlorogenic acid (5-O-caffeoylquinic acid), an ester of caffeic acid with quinic acid. Data also revealed that caffeic acid more effectively induced the downregulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein-1 (AP-1) and nuclear factor-kappaB transcription activity compared with chlorogenic acid. Fyn kinase activity was suppressed more effectively by caffeic acid than by chlorogenic acid, and downstream mitogen-activated protein kinases (MAPKs) were subsequently blocked. Pharmacological Fyn kinase inhibitor (3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and leflunomide) data also revealed that Fyn is involved in UVB-induced COX-2 expression mediated through the phosphorylation of MAPKs in JB6 P+ cells. Pull-down assays revealed that caffeic acid directly bound with Fyn and non-competitively with adenosine triphosphate. 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 agent against skin cancer.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Bong Jik
authors.initials: BJ
authors.lastname: Shin
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Mun Kyung
authors.initials: MK
authors.lastname: Hwang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002726:Chlorogenic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D003069:Coffee / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011801:Quinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D016588:Anticarcinogenic Agents; D002109:Caffeic Acids; D002726:Chlorogenic Acid; D003069:Coffee; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D007555:Isoxazoles; D000077339:Leflunomide; D051076:Proto-Oncogene Proteins c-fyn; D011743:Pyrimidines; D011801:Quinic Acid; C539297:3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine; C494957:FYN protein, human; C473200:5-caffeoylquinic acid; C040048:caffeic acid