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Article
Nature Medicine 10, 594 - 601 (2004)
Published online: 23 May 2004 | doi:10.1038/nm1052
mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways
Pradip K Majumder1,2, Phillip G Febbo1,2, Rachel Bikoff1,2, Raanan Berger1,2, Qi Xue1,2, Louis M McMahon3, Judith Manola1, James Brugarolas1,2, Timothy J McDonnell4, Todd R Golub1,2,5, Massimo Loda1,2, Heidi A Lane6 & William R Sellers1,2,5
Abstract
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-1
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-1, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 activity.
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