Scientific Publications

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

Publication TypeJournal Article
AuthorsMajumder, PK, Febbo PG, Bikoff R., Berger R., Xue Q., McMahon LM, Manola J., Brugarolas J., McDonnell TJ, Golub T. R., Loda M., Lane HA, and Sellers WR
AbstractLoss 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.
Year of Publication2004
JournalNature medicine
Volume10
Issue6
Pages594-601
Date Published (YYYY/MM/DD)2004/06/01
ISSN Number1078-8956
DOI10.1038/nm1052
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/15156201?dopt=Abstract