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. 2004 Jun;10(6):594-601.
doi: 10.1038/nm1052. Epub 2004 May 23.

mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways

Pradip K Majumder  1 , Phillip G Febbo, Rachel Bikoff, Raanan Berger, Qi Xue, Louis M McMahon, Judith Manola, James Brugarolas, Timothy J McDonnell, Todd R Golub, Massimo Loda, Heidi A Lane, William R Sellers
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mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways

Pradip K Majumder et al. Nat Med. 2004 Jun.

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 alpha 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 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.

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  • TORward AKTually useful mouse models.
    Mellinghoff IK, Sawyers CL. Mellinghoff IK, et al. Nat Med. 2004 Jun;10(6):579-80. doi: 10.1038/nm0604-579. Nat Med. 2004. PMID: 15170198 No abstract available.

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