mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apop
Author: ["Pradip K Majumder","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"]
Publication: Nature Medicine
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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.
Cite this article
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
