Title | Differential requirement of mTOR in postmitotic tissues and tumorigenesis. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Nardella C, Carracedo A, Alimonti A, Hobbs RM, Clohessy JG, Chen Z, Egia A, Fornari A, Fiorentino M, Loda M, Kozma SC, Thomas G, Cordon-Cardo C, Pandolfi PPaolo |
Journal | Sci Signal |
Volume | 2 |
Issue | 55 |
Pagination | ra2 |
Date Published | 2009 Jan 27 |
ISSN | 1937-9145 |
Keywords | Animals, Carrier Proteins, Cell Line, Transformed, Cell Proliferation, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Mitosis, Models, Biological, Multiprotein Complexes, Phosphotransferases (Alcohol Group Acceptor), Proteins, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Signal Transduction, TOR Serine-Threonine Kinases |
Abstract | The mammalian target of rapamycin (mTOR) is a crucial effector in a complex signaling network commonly disrupted in cancer. mTOR exerts its multiple functions in the context of two different multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Loss of the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) can hyperactivate mTOR through AKT and represents one of the most frequent events in human prostate cancer. We show here that conditional inactivation of mTor in the adult mouse prostate is seemingly inconsequential for this postmitotic tissue. Conversely, inactivation of mTor leads to a marked suppression of Pten loss-induced tumor initiation and progression in the prostate. This suppression is more pronounced than that elicited by the sole pharmacological abrogation of mTORC1. Acute inactivation of mTor in vitro also highlights the differential requirement of mTor function in proliferating and transformed cells. Collectively, our data constitute a strong rationale for developing specific mTOR inhibitors targeting both mTORC1 and mTORC2 for the treatment of tumors triggered by PTEN deficiency and aberrant mTOR signaling. |
DOI | 10.1126/scisignal.2000189 |
Alternate Journal | Sci Signal |
PubMed ID | 19176516 |
Grant List | P30 CA08748 / CA / NCI NIH HHS / United States R01 CA-82328 / CA / NCI NIH HHS / United States U01 CA-84292 / CA / NCI NIH HHS / United States R24CA83084 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.