West Kip A, Linnoila Ilona R, Belinsky Steven A, Harris Curtis C, Dennis Phillip A
Cancer Therapeutics Branch, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Cancer Res. 2004 Jan 15;64(2):446-51. doi: 10.1158/0008-5472.can-03-3241.
The role of the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway during tobacco carcinogen-induced transformation is unknown. To address this question, we evaluated this pathway in isogenic immortalized or tumorigenic human bronchial epithelial cells in vitro, as well as in progressive murine lung lesions induced by a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Compared with immortalized cells, tumorigenic cells had greater activation of the PI3K/Akt pathway, enhanced survival, and increased apoptosis in response to inhibition of the pathway. In vivo, increased activation of Akt and mammalian target of rapamycin was observed with increased phenotypic progression. Collectively, these results support the hypothesis that maintenance of Akt activity is necessary for survival of preneoplastic as well as transformed lung epithelial cells and suggest that inhibition of the PI3K/Akt pathway might be a useful approach to arrest lung tumorigenesis.
磷脂酰肌醇3'-激酶（PI3K）/Akt信号通路在烟草致癌物诱导的细胞转化过程中的作用尚不清楚。为了解决这个问题，我们在体外对同基因永生化或致瘤性人支气管上皮细胞以及由烟草特异性致癌物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮诱导的进行性小鼠肺部病变中的该信号通路进行了评估。与永生化细胞相比，致瘤性细胞具有更强的PI3K/Akt信号通路激活、更高的存活率以及在该信号通路受到抑制时凋亡增加。在体内，随着表型进展的增加，观察到Akt和雷帕霉素哺乳动物靶标的激活增加。总体而言，这些结果支持以下假设：维持Akt活性对于肿瘤前和转化的肺上皮细胞的存活是必要的，并表明抑制PI3K/Akt信号通路可能是阻止肺肿瘤发生的一种有效方法。
