Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity.
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.
Lee
Kyung Mi
KM
The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
Lee
Ki Won
KW
Jung
Sung Keun
SK
Lee
Eun Jung
EJ
Heo
Yong-Seok
YS
Bode
Ann M
AM
Lubet
Ronald A
RA
Lee
Hyong Joo
HJ
Dong
Zigang
Z
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
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