Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity

• Published in: Biochemical pharmacology Vol. 80; no. 12; pp. 2042 - 2049
• Main Authors: Lee, Kyung Mi, Lee, Ki Won, Jung, Sung Keun, Lee, Eun Jung, Heo, Yong-Seok, Bode, Ann M., Lubet, Ronald A., Lee, Hyong Joo, Dong, Zigang
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier Inc 15-12-2010; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Animals; Anticarcinogenic Agents - pharmacology; ATP; Binding, Competitive; Biological and medical sciences; Cell Line; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 Inhibitors - pharmacology; Dermatology; Female; Flavonoid; In Vitro Techniques; Kaempferols - pharmacology; Medical sciences; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases - metabolism; Models, Molecular; Pharmacology. Drug treatments; Phosphorylation; Photo-carcinogenesis; Skin - drug effects; Skin - enzymology; Skin cancer; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Transcription Factor AP-1 - metabolism; Tumors of the skin and soft tissue. Premalignant lesions; Ultraviolet Rays - adverse effects; Flavonoid; Photo-carcinogenesis; Skin cancer; Skin disease; Enzyme; Kaempferol; UVB radiation; Cyclooxygenase 2; Malignant tumor; Carcinogenesis; Biological activity; Polyphenol; Phenols; Inhibitor; Skin; Oxidoreductases; Cancer
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2010.06.042

Hypothetical computational models of Src in complex with kaempferol. Our results suggest that kaempferol is a potent chemopreventive agent against skin cancer through its inhibitory interaction with Src.
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.