The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
Biochem Pharmacol. 2010 Dec 15;80(12):2042-9. doi: 10.1016/j.bcp.2010.06.042. Epub 2010 Jul 1.
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.
紫外线 (UV) 辐射是皮肤非黑色素瘤癌发展的主要环境风险因素，而 UVB 尤其通过各种信号通路促进肿瘤生长。具有抗炎和抗氧化特性的类黄酮槲皮素已被研究作为化学预防剂；然而，关于其对 UVB 诱导的光致癌作用的影响知之甚少。在这里，我们研究了槲皮素对 UVB 诱导的皮肤炎症的影响。我们发现，槲皮素抑制了 UVB 诱导的小鼠皮肤表皮 JB6 P+细胞中环氧化酶-2 (COX-2) 蛋白的表达，并减弱了 cox-2 和激活蛋白-1 (AP-1) 的 UVB 诱导转录活性。槲皮素减弱了几种丝裂原活化蛋白激酶 (MAPKs) 的磷酸化，包括 ERKs、p38 和 JNKs，但对上游 MAPK 调节剂Src 的磷酸化没有影响。然而，体外和离体激酶测定表明，槲皮素抑制了 Src 激酶活性。此外，来自小鼠皮肤的体内数据支持这样一种观点，即槲皮素通过阻断 Src 激酶活性来抑制 UVB 诱导的 COX-2 表达。下拉测定显示，槲皮素与 ATP 竞争直接结合 Src。对接数据表明，槲皮素很容易进入 Src 激酶结构域的 ATP 结合位点，该位点位于 N 结构域和 C 结构域之间。综上所述，这些结果表明，槲皮素通过与 Src 的抑制相互作用，成为一种有效的皮肤癌化学预防剂。
