Abstract
mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Finally, we show that the development of prostate cancer caused by Pten deletion specifically in prostate epithelium requires mTORC2, but that for normal prostate epithelial cells, mTORC2 activity is nonessential. The selective requirement for mTORC2 in tumor development suggests that mTORC2 inhibitors may be of substantial clinical utility.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Transformation, Neoplastic
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Cells, Cultured
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Epithelial Cells / pathology
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Epithelial Cells / physiology
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Fibroblasts / cytology
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Fibroblasts / physiology
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Phenotype
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Prostate / cytology
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Prostate / metabolism
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Prostate / pathology
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / physiopathology*
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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 c-akt / metabolism
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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RNA Interference
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Rapamycin-Insensitive Companion of mTOR Protein
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Signal Transduction / physiology
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TOR Serine-Threonine Kinases
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transplantation, Heterologous
Substances
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Carrier Proteins
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Rapamycin-Insensitive Companion of mTOR Protein
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Transcription Factors
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rictor protein, mouse
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Protein Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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MTOR protein, human
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mTOR protein, mouse
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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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PTEN Phosphohydrolase
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Pten protein, mouse