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 pathwaysPradip 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, 51
Departments of Medical Oncology, Pediatric Oncology and Biostatistical Sciences, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. 2
Departments of Medicine and Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. 3
Novartis Pharmaceutical Corporation, One Health Plaza, East Hanover, New Jersey 07936, USA. 4
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. 5
The Broad Institute at Harvard and MIT, 320 Charles Street, Cambridge, Massachusetts 02142, USA. 6
Novartis Institute for Biomedical Research, Oncology, CH-4002 Basel, Switzerland.
Correspondence should be addressed to William R Sellers william_sellers@dfci.harvard.eduLoss 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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