|Publication Type||Journal Article|
|Year of Publication||2004|
|Authors||Majumder, 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|
|Date Published||2004 Jun|
|Keywords||Animals, 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|
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.
|Alternate Journal||Nat. Med.|
|Grant List||P01CA89021 / CA / NCI NIH HHS / United States|