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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2004-5-31
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/AKT1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/HIF1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Placebos,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Sirolimus,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/everolimus,
http://linkedlifedata.com/resource/pubmed/chemical/mTOR protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1078-8956
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pubmed:author |
pubmed-author:BergerRaananR,
pubmed-author:BikoffRachelR,
pubmed-author:BrugarolasJamesJ,
pubmed-author:FebboPhillip GPG,
pubmed-author:GolubTodd RTR,
pubmed-author:LaneHeidi AHA,
pubmed-author:LodaMassimoM,
pubmed-author:MajumderPradip KPK,
pubmed-author:ManolaJudithJ,
pubmed-author:McDonnellTimothy JTJ,
pubmed-author:McMahonLouis MLM,
pubmed-author:SellersWilliam RWR,
pubmed-author:XueQiQ
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pubmed:issnType |
Print
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pubmed:volume |
10
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
594-601
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15156201-Animals,
pubmed-meshheading:15156201-Apoptosis,
pubmed-meshheading:15156201-Cell Survival,
pubmed-meshheading:15156201-Epithelial Cells,
pubmed-meshheading:15156201-Gene Expression Profiling,
pubmed-meshheading:15156201-Humans,
pubmed-meshheading:15156201-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:15156201-Immunosuppressive Agents,
pubmed-meshheading:15156201-In Situ Nick-End Labeling,
pubmed-meshheading:15156201-Male,
pubmed-meshheading:15156201-Mice,
pubmed-meshheading:15156201-Mice, Inbred C57BL,
pubmed-meshheading:15156201-Mice, Transgenic,
pubmed-meshheading:15156201-Phenotype,
pubmed-meshheading:15156201-Placebos,
pubmed-meshheading:15156201-Prostate,
pubmed-meshheading:15156201-Prostatic Neoplasms,
pubmed-meshheading:15156201-Protein Kinase Inhibitors,
pubmed-meshheading:15156201-Protein Kinases,
pubmed-meshheading:15156201-Protein-Serine-Threonine Kinases,
pubmed-meshheading:15156201-Proto-Oncogene Proteins,
pubmed-meshheading:15156201-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:15156201-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:15156201-Signal Transduction,
pubmed-meshheading:15156201-Sirolimus,
pubmed-meshheading:15156201-TOR Serine-Threonine Kinases,
pubmed-meshheading:15156201-Transcription Factors
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pubmed:year |
2004
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pubmed:articleTitle |
mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.
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pubmed:affiliation |
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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