Ouyang Weiming, Li Jingxia, Ma Qian, Huang Chuanshu
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Carcinogenesis. 2006 Apr;27(4):864-73. doi: 10.1093/carcin/bgi321. Epub 2005 Dec 29.
Skin is a major target of carcinogenic trivalent arsenic (arsenite, As3+). It has been thought that cell proliferation is one of the central events involved in the carcinogenic effect of arsenite. Cyclin D1, a nuclear protein playing a pivotal role in cell proliferation and cell cycle transition from G1 to S phases, has been reported to be induced in human fibroblast by arsenite via uncertain molecular mechanisms. In the present study, the potential roles of PI-3K/Akt/IKKbeta/NFkappaB signal pathway in cyclin D1 induction by arsenite were addressed in mouse epidermal Cl41 cells. We found that exposure of Cl41 cells to arsenite was able to induce cell proliferation, activate PI-3K-->Akt/p70(S6k) signal pathway and increase cyclin D1 expression at both transcription and protein levels. Pre-treatment of Cl41 cells with PI-3K inhibitor, wortmannin, significantly inhibited the phosphorylation of Akt and p70(S6k) and thereby dramatically impaired the cyclin D1 induction by arsenite, implicating the importance of the PI-3K signal pathway in the cyclin D1 induction by arsenite. Furthermore, inhibition of PI-3K/Akt by overexpression of Deltap85 or DN-Akt blocked arsenite-induced IKK phosphorylation, IkappaBalpha degradation and cyclin D1 expression, indicating that IKK/NFkappaB is the downstream transducer of arsenite-triggered PI-3K/Akt cascade. Moreover, inhibition of IKKbeta/NFkappaB signal pathway by overexpression of its dominant negative mutant, IKKbeta-KM, also significantly blocked arsenite-induced cyclin D1 expression. Overall, arsenite exposure triggered PI-3K/Akt/IKKbeta/NFkappaB signal cascade which in turn plays essential roles in inducing cyclin D1 expression.
皮肤是致癌性三价砷（亚砷酸盐，As3+）的主要靶器官。人们一直认为细胞增殖是亚砷酸盐致癌作用的核心事件之一。细胞周期蛋白D1是一种在细胞增殖以及细胞从G1期到S期的周期转换中起关键作用的核蛋白，据报道，亚砷酸盐可通过不确定的分子机制在人成纤维细胞中诱导其表达。在本研究中，我们探讨了PI-3K/Akt/IKKβ/NFκB信号通路在亚砷酸盐诱导细胞周期蛋白D1表达中的潜在作用，研究对象为小鼠表皮Cl41细胞。我们发现，Cl41细胞暴露于亚砷酸盐能够诱导细胞增殖，激活PI-3K→Akt/p70(S6k)信号通路，并在转录和蛋白水平上增加细胞周期蛋白D1的表达。用PI-3K抑制剂渥曼青霉素预处理Cl41细胞，可显著抑制Akt和p70(S6k)的磷酸化，从而极大地削弱亚砷酸盐对细胞周期蛋白D1的诱导作用，这表明PI-3K信号通路在亚砷酸盐诱导细胞周期蛋白D1表达中具有重要作用。此外，通过过表达Δp85或显性负性Akt（DN-Akt）抑制PI-3K/Akt可阻断亚砷酸盐诱导的IKK磷酸化、IκBα降解和细胞周期蛋白D1表达，表明IKK/NFκB是亚砷酸盐触发的PI-3K/Akt级联反应的下游转导分子。此外，过表达其显性负性突变体IKKβ-KM抑制IKKβ/NFκB信号通路，也可显著阻断亚砷酸盐诱导的细胞周期蛋白D1表达。总体而言，亚砷酸盐暴露触发了PI-3K/Akt/IKKβ/NFκB信号级联反应，这反过来又在诱导细胞周期蛋白D1表达中发挥重要作用。
