title: Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity.
abstract: Ultraviolet (UV) radiation is the primary environmental risk factor in the development of nonmelanoma skin cancer, and UVB in particular promotes tumor growth through various signaling pathways. Kaempferol, a flavonoid with anti-inflammatory and anti-oxidative properties, has been studied as a chemopreventive agent; however, little is known regarding its effects on UVB-induced photo-carcinogenesis. Here, we examined the effect of kaempferol on UVB-induced skin inflammation. We found that kaempferol suppressed UVB-induced cyclooxygenase-2 (COX-2) protein expression in mouse skin epidermal JB6 P+ cells and attenuated the UVB-induced transcriptional activities of cox-2 and activator protein-1 (AP-1). Kaempferol attenuated the UVB-induced phosphorylation of several mitogen-activated protein kinases (MAPKs), including ERKs, p38, and JNKs, but had no effect on the phosphorylation of the upstream MAPK regulator Src. However, in vitro and ex vivo kinase assays demonstrated that kaempferol suppressed Src kinase activity. Furthermore, in vivo data from mouse skin support the idea that kaempferol suppresses UVB-induced COX-2 expression by blocking Src kinase activity. A pull-down assay revealed that kaempferol competes with ATP for direct binding to Src. Docking data suggest that kaempferol docks easily into the ATP-binding site of Src, which is located between the N and the C lobes of the kinase domain. Taken together, these results suggest that kaempferol is a potent chemopreventive agent against skin cancer through its inhibitory interaction with Src.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
authors.forename: Kyung Mi
authors.initials: KM
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D044949:Kaempferols / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D012867:Skin / Q000187:drug effects* / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D044949:Kaempferols; D018808:Transcription Factor AP-1; D000255:Adenosine Triphosphate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases