Nitric Oxide-Mediated Bcl-2 Stabilization Potentiates Malignant Transformation of Human Lung Epithelial Cells
Nitric Oxide-Mediated Bcl-2 Stabilization Potentiates Malignant Transformation of Human Lung Epithelial Cells
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DOI：
10.1165/rcmb.2009-0094oc
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发表时间：
2010-05-01
影响因子：
6.4
通讯作者：
Rojanasakul, Yon
中科院分区：
文献类型：
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作者：
Azad, Neelam;Iyer, Anand Krishnan V.;Rojanasakul, Yon
六价铬(六价铬)化合物是已知的人类致癌物质，与肺癌的发病率有关。虽然铬(VI)暴露与肺癌之间的直接相关性已经被确定，但一些旨在建立铬(VI)动物模型的研究已经产生了不一致的数据，这些数据并不肯定地支持流行病学研究的结果。由于缺乏良好的动物模型，阻碍了对铬(VI)暴露所涉及的分子机制的识别，我们开发了一种体外模型，以促进对铬(VI)诱导的致癌机制的研究。我们在这里报道，长期暴露于铬(VI)会导致非致瘤性人肺上皮细胞的恶性转化。与传代相匹配的对照细胞相比，铬(VI)转化的细胞表现出接触抑制消失、克隆形成、细胞侵袭、迁移和增殖率增加。铬(VI)转化的细胞通过S亚硝化和一氧化氮依赖的稳定Bcl2蛋白的机制来逃避凋亡。本研究建立了一个重要的体外模型，促进了铬(VI)诱导的致癌机制的研究，并阐明了一种新的机制，即导致非致癌肺细胞对人类致癌物的应答而发生抗凋亡的恶性转化。
Hexavalent chromium (Cr(VI)) compounds are known human carcinogens associated with the incidence of lung cancer. Although a direct correlation between Cr(VI) exposure and lung cancer has been established, several studies aimed at generating animal models for Cr(VI) have yielded inconsistent data that do not affirmatively support findings from epidemiologic studies. Because the lack of a good animal model has hindered the identification of molecular mechanisms involved in Cr(VI) exposure, we developed an in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis. We report here that long-term exposure to Cr(VI) leads to the malignant transformation of nontumorigenic human lung epithelial cells. Cr(VI)-transformed cells exhibited loss of contact inhibition, colony formation, and increased rates of cell invasion, migration, and proliferation, as compared with passage-matched control cells. Cr(VI)-transformed cells evaded apoptosis by a mechanism involving S-nitrosylation and stabilization of Bcl-2 protein in a nitric oxide dependent manner. This study establishes an important in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis, and elucidates a novel mechanism that causes apoptosis-resistant malignant transformation of nontumorigenic lung cells in response to a human carcinogen.