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

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

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Figure 1: An mTOR inhibitor (RAD001) reverses the PIN phenotype of AKT1-Tg mice.
Figure 2: Selective in vivo inactivation of mTOR and S6K activity by RAD001.
Figure 3: Time course of the phenotypic response to mTOR inhibition.
Figure 4: Induction of cell death by mTOR inhibition in AKT1-Tg mice.
Figure 5: Complete phenotype regression after mTOR inhibition requires the mitochondrial apoptosis pathway.
Figure 6: Expression profiles of mTOR inhibition are enriched for Hif-1α targets and glycolysis genes.

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Acknowledgements

We thank M.A. Brown and W.G. Kaelin for critical comments; J. Shim, N. Bhattacharya, A. Thorner and S. Luo for technical assistance; and J. Pouyssegur for the Hif-1 antibody. This work was supported the Linda and Arthur Gelb Center for Translational Research, by the National Cancer Institute (PO1CA89021), by CaPCURE, by the Damon-Runyon Cancer Research Foundation (W.R.S.) and by a Career Development Award from the DF/HCC SPORE in Prostate Cancer (P.K.M.).

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Correspondence to William R Sellers.

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W.R.S. and M.L. receive research support from and are consultants for the Novartis Institute of Biomedical Research. H.A.L. is an employee of the Novartis Institute of Biomedical Research. L.M.M. is an employee of Novartis Pharmaceutical Corporation.

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Majumder, P., Febbo, P., Bikoff, R. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10, 594–601 (2004). https://doi.org/10.1038/nm1052

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