mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways
mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways
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DOI：
10.1038/nm1052
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发表时间：
2004-06-01
期刊：
影响因子：
82.9
通讯作者：
Sellers, WR
中科院分区：
文献类型：
--
作者：
Majumder, PK;Febbo, PG;Sellers, WR
PTEN功能的丧失导致磷酸肌醇3-激酶（PI3K）信号传导和AKT的激活。现在，临床试验正在测试雷帕霉素（MTOR）抑制的哺乳动物靶标是否有助于治疗PTEN-NULL癌症。在这里，我们报告说，MTOR抑制作用诱导上皮细胞的凋亡以及在前列腺中表达人Akt1的小鼠的肿瘤表型的完全逆转。细胞死亡的诱导需要线粒体途径，因为Bcl2的前列腺特异性共表达阻塞了细胞凋亡。因此，AKT下游需要一个依赖MTOR的生存信号。然而，在MTOR抑制作用的情况下，BCL2表达仅部分恢复了腔内细胞的生长。表达分析表明，HIF-1Alpha靶标，包括编码大多数糖酵解酶的基因，构成了对AKT激活和MTOR抑制的主要转录反应。这些数据表明，Akt驱动的前列腺上皮细胞的扩展需要MTOR依赖性的存活信号和HIF-1Alpha的激活，并且对MTOR抑制剂的临床耐药性可能会通过BCL2表达和/或HIF-1Alpha活性的上调来出现。
Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1alpha activity.