Luteolin Inhibits Protein Kinase Cε and c-Src Activities and UVB-Induced Skin Cancer
Luteolin Inhibits Protein Kinase Cε and c-Src Activities and UVB-Induced Skin Cancer
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DOI：
10.1158/0008-5472.can-09-4093
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
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作者：
Byun, Sanguine;Lee, Ki Won;Dong, Zigang
木犀草素是一种黄酮类化合物，存在于洋葱和西兰花等多种蔬菜中，据报道具有抗癌作用。然而，其对紫外线诱发的皮肤癌的化学预防作用及其机制尚不完全清楚。在此，我们研究了木犀草素在 JB6 P+ 细胞系和 SKH-1 无毛小鼠模型中的化学预防作用和相关机制。木犀草素抑制 JB6 P+ 细胞中 UVB 诱导的环氧合酶 2 表达以及激活蛋白 1 和核因子 -κ B 活性。免疫印迹和激酶测定数据表明，木犀草素可减弱蛋白激酶 C epsilon (PKC epsilon) 和 Src 激酶活性，随后抑制 UVB 诱导的丝裂原激活蛋白激酶磷酸化和 Akt 信号通路。此外，pull-down 测定表明，木犀草素以 ATP 竞争性方式直接与 PKC epsilon 和 Src 结合。重要的是，木犀草素抑制了 SKH-1 无毛小鼠的肿瘤发生率、多样性和整体大小。通过免疫组织化学和免疫印迹对皮肤进行的分析表明，与仅接受 UVB 治疗的组相比，木犀草素治疗组的环氧合酶 2、肿瘤坏死因子 α 和增殖细胞核抗原的水平显着降低。使用皮肤裂解物的进一步分析表明，木犀草素抑制 PKC epsilon 和 Src 激酶活性。总之，这些数据表明，木犀草素主要通过靶向 PKC epsilon 和 Src 对 UVB 诱导的皮肤癌发挥有效的化学预防活性。癌症研究； 70(6)； 2415-23。 (C)2010 AACR。
Luteolin, a flavonoid present in various vegetables including onion and broccoli, has been reported to possess anticarcinogenic effects. However, its chemopreventive effect on UV-induced skin cancer and its mechanism are not fully understood. Herein, we examined the chemopreventive effect and associated mechanisms of luteolin in the JB6 P+ cell line and the SKH-1 hairless mouse model. Luteolin suppressed UVB-induced cyclooxygenase-2 expression and activator protein-1 and nuclear factor-kappa B activity in JB6 P+ cells. Immunoblot and kinase assay data showed that luteolin attenuated protein kinase C epsilon (PKC epsilon) and Src kinase activities and subsequently inhibited UVB-induced phosphorylation of mitogen-activated protein kinases and the Akt signaling pathway. In addition, pull-down assays revealed that luteolin binds directly to PKC epsilon and Src in an ATP-competitive manner. Importantly, luteolin suppressed tumor incidence, multiplicity, and overall size in SKH-1 hairless mice. Analysis of the skin by immunohistochemistry and immunoblotting showed that luteolin-treated groups had a substantial reduction in the levels of cyclooxygenase-2, tumor necrosis factor-alpha, and proliferating cell nuclear antigen compared with groups treated with only UVB. Further analysis using skin lysates showed that luteolin inhibited PKC epsilon and Src kinase activity. Together, these data suggest that luteolin exerts potent chemopreventive activity against UVB-induced skin cancer mainly by targeting PKC epsilon and Src. Cancer Res; 70(6); 2415-23. (C)2010 AACR.