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Nat Med DOI:10.1038/nm1052

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

Publication TypeJournal Article
Year of Publication2004
AuthorsMajumder, PK, Febbo, PG, Bikoff, R, Berger, R, Xue, Q, McMahon, LM, Manola, J, Brugarolas, J, McDonnell, TJ, Golub, TR, Loda, M, Lane, HA, Sellers, WR
JournalNat Med
Volume10
Issue6
Pages594-601
Date Published2004 Jun
ISSN1078-8956
KeywordsAnimals, Apoptosis, Cell Survival, Epithelial Cells, Everolimus, Gene Expression Profiling, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunosuppressive Agents, In Situ Nick-End Labeling, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Placebos, Prostate, Prostatic Neoplasms, Protein Kinase Inhibitors, Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Transcription Factors
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.

URLhttp://dx.doi.org/10.1038/nm1052
DOI10.1038/nm1052
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/15156201?dopt=Abstract

Alternate JournalNat. Med.
PubMed ID15156201
Grant ListP01CA89021 / CA / NCI NIH HHS / United States