Li Jingxia, Tang Moon-shong, Liu Bingci, Shi Xianglin, Huang Chuanshu
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Oncogene. 2004 May 13;23(22):3932-44. doi: 10.1038/sj.onc.1207501.
Mouse skin tumorigenicity studies indicate that benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) contributes to carcinogenesis as both a tumor initiator and promoter. However, the mechanisms that mediate B[a]PDE tumor promotion effects remain unclear. Our results demonstrated that in mouse epidermal Cl41 cells, B[a]PDE treatment resulted in marked activation of AP-1 and its upstream MAPKs, including ERKs, JNKs and p38K. B[a]PDE exposure also led to activation of phosphotidylinositol 3-kinase (PI-3K), Akt and p70 S6 kinase (p70S6k). B[a]PDE-induced AP-1 transactivation was inhibited by pretreatment of cells with PI-3K inhibitors, wortmannin or Ly294002. In contrast, inhibition of p70S6k with rapamycin did not show any inhibitory effects. An overexpression of dominant-negative mutant of PI-3K, Deltap85, impaired B[a]PDE-induced activation of PI-3K, Akt and AP-1 transactivation. Furthermore, an overexpression of dominant-negative Akt mutant, Akt-T308A/S473A, blocked B[a]PDE-induced activation of Akt, AP-1 and JNKs, while it did not affect the activation of p70S6k, ERKs and p38 kinase. These results demonstrated that B[a]PDE was able to induce AP-1 transactivation and this AP-1 induction was specific through PI-3K/Akt/JNKs-dependent and p70S6k-independent pathways. This study also indicated that Akt-T308A/S473A blocks B[a]PDE-induced AP-1 activation specific through impairing JNK pathway. These findings will help us to understand the signal transduction pathways involved in the carcinogenic effects of B[a]PDE.
小鼠皮肤致瘤性研究表明，苯并[a]芘 - 7,8 - 二醇 - 9,10 - 环氧化物（B[a]PDE）作为肿瘤起始剂和促进剂均对致癌作用有贡献。然而，介导B[a]PDE肿瘤促进作用的机制仍不清楚。我们的结果表明，在小鼠表皮Cl41细胞中，B[a]PDE处理导致AP - 1及其上游丝裂原活化蛋白激酶（MAPK）显著激活，包括细胞外信号调节激酶（ERK）、应激活化蛋白激酶（JNK）和p38激酶（p38K）。B[a]PDE暴露还导致磷脂酰肌醇3 - 激酶（PI - 3K）、蛋白激酶B（Akt）和p70核糖体蛋白S6激酶（p70S6k）激活。用PI - 3K抑制剂渥曼青霉素或LY294002预处理细胞可抑制B[a]PDE诱导的AP - 1反式激活。相反，用雷帕霉素抑制p70S6k未显示任何抑制作用。PI - 3K的显性负突变体Deltap85的过表达损害了B[a]PDE诱导的PI - 3K、Akt激活及AP - 1反式激活。此外，显性负Akt突变体Akt - T308A/S473A的过表达阻断了B[a]PDE诱导的Akt、AP - 1和JNK激活，而不影响p70S6k、ERK和p38激酶的激活。这些结果表明，B[a]PDE能够诱导AP - 1反式激活，且这种AP - 1诱导通过PI - 3K/Akt/JNK依赖性和p70S6k非依赖性途径具有特异性。本研究还表明，Akt - T308A/S473A通过损害JNK途径特异性阻断B[a]PDE诱导的AP - 1激活。这些发现将有助于我们理解参与B[a]PDE致癌作用的信号转导途径。
