Huang C, Zhang Q, Li J, Shi X, Castranova V, Ju G, Costa M, Dong Z
Nelson Institute of Environmental Medicine, New York University School of Medicine, NY 10016, USA.
Mol Cell Biochem. 2001 Jun;222(1-2):141-7. doi: 10.1023/a:1017953927347.
Cadmium is a potent and effective carcinogen in rodents and has recently been accepted by IARC (International Agency for Research on Cancer) as a category I carcinogen. Cadmium-induced up-regulation of intracellular signaling pathways leading to increased mitogenesis is thought to be a major mechanism for the carcinogenic activity following chronic cadmium exposure. In the present study, we found that exposure of cells to cadmium induced significant activation of AP-1 and all three members of the MAP kinase family in mouse epidermal JB6 cells. The induction of AP-1 activity by cadmium appears to involve activation of Erks, since the induction of AP-1 activity by cadmium was blocked by pretreatment of cells with PD98058. Interestingly, the induction of AP-1 by cadmium was greatly enhanced by the chemical tumor promoter, TPA and the growth factor EGF, but not by ultraviolet C radiation. In vivo studies demonstrated that cadmium could also induce transactivation of AP-1 in AP-1-luciferase report transgenic mice. Considering the role of AP-1 activation in tumor promotion, the results presented in this study provide a possible molecular mechanism for cadmium-induced carcinogenesis.
镉在啮齿动物中是一种强效且有效的致癌物，最近已被国际癌症研究机构（IARC）认定为I类致癌物。镉诱导细胞内信号通路上调导致有丝分裂增加，这被认为是慢性镉暴露后致癌活性的主要机制。在本研究中，我们发现将细胞暴露于镉会在小鼠表皮JB6细胞中诱导AP - 1以及丝裂原活化蛋白激酶（MAP）家族的所有三个成员显著激活。镉对AP - 1活性的诱导似乎涉及细胞外信号调节激酶（Erks）的激活，因为用PD98058预处理细胞可阻断镉对AP - 1活性的诱导。有趣的是，化学肿瘤启动子佛波酯（TPA）和生长因子表皮生长因子（EGF）可大大增强镉对AP - 1的诱导，但紫外线C辐射则不能。体内研究表明，镉还可在AP - 1 - 荧光素酶报告转基因小鼠中诱导AP - 1的反式激活。考虑到AP - 1激活在肿瘤促进中的作用，本研究结果为镉诱导的致癌作用提供了一种可能的分子机制。
