Akt1 deletion prevents lung tumorigenesis by mutant K-ras.
Akt1 deletion prevents lung tumorigenesis by mutant K-ras.
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DOI：
10.1038/onc.2010.556
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发表时间：
2011-04-14
期刊：
影响因子：
8
通讯作者：
Dennis, P. A.
中科院分区：
文献类型：
--
作者：
Hollander, M. C.;Maier, C. R.;Hobbs, E. A.;Ashmore, A. R.;Linnoila, R. I.;Dennis, P. A.
K-ras基因突变与吸烟诱发的肺癌和不良临床结局相关。在小鼠中，K-ras突变足以诱导肺肿瘤，其需要磷酸肌醇-3-激酶（PI 3 K）和进一步下游的哺乳动物雷帕霉素靶（mTOR）活化。然而，连接PI 3 K和mTOR的单个Akt亚型的作用尚不清楚。在这里，我们表明，Akt 1的缺失，而不是Akt 2或Akt 3防止在烟草致癌物诱导的模型和遗传模型肺肿瘤的发生。Akt 1缺失阻止了肿瘤的发生以及肿瘤的进展，与肿瘤组织中Akt信号的减少一致。相反，Akt 3的缺失增加了致癌物模型中的肿瘤多样性，并增加了遗传模型中的肿瘤大小。缺乏Akt 1的成纤维细胞对突变型K-ras的转化和表皮生长因子的刺激具有抗性。K-ras突变和Akt 1水平降低的人肺癌细胞不能在体内生长。这些数据表明，Akt 1是肺肿瘤中突变K-ras激活的主要Akt亚型，Akt 3可能在肺肿瘤发生和肺肿瘤进展中对抗Akt 1。鉴于Akt抑制剂在临床开发中作为癌症治疗剂不是同种型选择性的，这些研究支持特异性靶向Akt 1以减轻突变型K-ras在肺癌中的作用。
K-ras mutations are associated with smoking-induced lung cancer and poor clinical outcomes. In mice, K-ras mutations are sufficient to induce lung tumors, which require phosphoinoside-3-kinase (PI3K) and further downstream, mammalian target of rapamycin (mTOR) activation. However, the roles of individual Akt isoforms that link PI3K and mTOR are unknown. Here, we show that deletion of Akt1 but not Akt2 or Akt3 prevents lung tumorigenesis in a tobacco carcinogen-induced model and a genetic model. Akt1 deletion prevented tumor initiation as well as tumor progression, coincident with decreased Akt signaling in tumor tissues. In contrast, deletion of Akt3 increased tumor multiplicity in the carcinogen model and increased tumor size in the genetic model. Fibroblasts lacking Akt1 are resistant to transformation by mutant K-ras and stimulation by epidermal growth factor. Human lung cancer cells with mutant K-ras and diminished Akt1 levels fail to grow in vivo. These data suggest that Akt1 is the primary Akt isoform activated by mutant K-ras in lung tumors, and that Akt3 may oppose Akt1 in lung tumorigenesis and lung tumor progression. Given that Akt inhibitors in clinical development as cancer therapeutics are not isoform selective, these studies support specific targeting of Akt1 to mitigate the effects of mutant K-ras in lung cancer.
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影响因子：
30.8
作者：
Hollander, MC;Sheikh, MS;Fornace, AJ
通讯作者：
Fornace, AJ
影响因子：
8.8
作者：
Davies, M. A.;Stemke-Hale, K.;Tellez, C.;Calderone, T. L.;Deng, W.;Prieto, V. G.;Lazar, A. J. F.;Gershenwald, J. E.;Mills, G. B.
通讯作者：
Mills, G. B.
影响因子：
5.3
作者：
Easton, RM;Cho, H;Birnbaum, MJ
通讯作者：
Birnbaum, MJ
影响因子：
10.5
作者：
Chen, Mei-Ling;Xu, Pei-Zhang;Hay, Nissim
通讯作者：
Hay, Nissim
DOI：
10.4161/cc.8.16.9335
发表时间：
2009-08-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Gonzalez E;McGraw TE
通讯作者：
McGraw TE