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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology*
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Cell Survival
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Epithelial Cells / metabolism*
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Everolimus
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Gene Expression Profiling
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunosuppressive Agents / metabolism
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In Situ Nick-End Labeling
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Phenotype
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Placebos
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Prostate / cytology
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Prostate / metabolism
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Protein Kinase Inhibitors
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction / physiology*
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Sirolimus / analogs & derivatives
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Sirolimus / metabolism
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TOR Serine-Threonine Kinases
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunosuppressive Agents
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Placebos
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Transcription Factors
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Everolimus
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus