Inhibition of TPA-induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes.
Inhibition of TPA-induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes.
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芹菜素通过下调人角质形成细胞中的 Akt 信号转导来抑制 TPA 诱导的环氧合酶 2 (COX-2) 表达。
DOI：
10.1002/mc.20123
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Pelling,JillC
中科院分区：
文献类型：
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作者：
VanDross,RukiyahT;Hong,Xiaoman;Pelling,JillC
芹菜素是一种非致突变生物活性物质，已被证明是由二甲基苯并蒽（DMBA）和12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）引发和促进的两阶段方案诱导的小鼠皮肤致癌作用的抑制剂。这些DMBA/TPA诱导的鳞状细胞癌过表达环氧合酶-2（考克斯-2）。环氧合酶是合成前列腺素（PG）的关键酶，将磷脂酶A2释放的花生四烯酸（AA）转化为前列腺素。大量证据表明，诱导型环氧合酶考克斯-2参与多种组织类型（包括结肠、乳腺、肺和皮肤）的肿瘤促进和癌变。在本研究中，我们已经确定芹菜素抑制TPA诱导的人角质形成细胞系HaCaT中考克斯-2蛋白和mRNA的增加。TPA诱导的考克斯-2诱导与Akt激酶活化增加相关，用PI 3激酶抑制剂LY 294002处理细胞可阻断TPA诱导的考克斯-2。在用TPA和芹菜素处理的细胞中，考克斯-2表达的抑制与Akt激酶活化的抑制相关。芹菜素介导的TPA诱导的考克斯-2表达的抑制通过瞬时转染组成型活性Akt（CA-Akt）逆转。MEK（PD 98059）、p38（SB 202190）的化学抑制剂（但非JNK（SP 600125））阻断TPA对考克斯-2的诱导，尽管芹菜素并不通过这些途径抑制TPA介导的考克斯-2表达。TPA诱导的AA从HaCaT细胞的释放也被用芹菜素处理的细胞抑制。这些数据表明，芹菜素通过阻断Akt的信号转导抑制TPA-介导的考克斯-2表达，芹菜素还阻断AA释放，这可能有助于其化学预防活性。© 2005 Wiley‐利斯公司
Apigenin is a nonmutagenic bioflavonoid that has been shown to be an inhibitor of mouse skin carcinogenesis induced by the two‐stage regimen of initiation and promotion with dimethylbenzanthracene (DMBA) and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). These DMBA/TPA‐induced squamous cell carcinomas overexpress cyclooxygenase‐2 (COX‐2). Cyclooxygenases are key enzymes required for prostaglandin (PG) synthesis, converting the arachidonic acid (AA) released by phospholipase A2 into prostaglandins. A large body of evidence indicates that the inducible form of cyclooxygenase, COX‐2, is involved in tumor promotion and carcinogenesis in a wide variety of tissue types, including colon, breast, lung, and skin. In the present study, we have determined that apigenin inhibited the TPA‐induced increase in COX‐2 protein and mRNA in the human keratinocyte cell line; HaCaT. The induction of COX‐2 elicited by TPA correlated with increased activation of Akt kinase and cell treatment with the PI3 kinase inhibitor, LY294002, blocked TPA induction of COX‐2. In cells treated with TPA and apigenin, the inhibition of COX‐2 expression correlated with inhibition of Akt kinase activation. Apigenin‐mediated inhibition of TPA‐induced COX‐2 expression was reversed by transient transfection with constitutively active Akt (CA‐Akt). Chemical inhibitors of MEK (PD98059), p38 (SB202190), but not JNK (SP600125) blocked TPA induction of COX‐2 although apigenin did not inhibit TPA‐mediated COX‐2 expression through these pathways. The TPA‐induced release of AA from HaCaT cells was also inhibited by cell treatment with apigenin. These data show that apigenin inhibits TPA‐mediated COX‐2 expression by blocking signal transduction of Akt and that apigenin also blocks AA release, which may contribute to its chemopreventive activity. © 2005 Wiley‐Liss, Inc.