title: Differential requirement of mTOR in postmitotic tissues and tumorigenesis.
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.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Caterina
authors.initials: C
authors.lastname: Nardella
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: John G
authors.initials: JG
authors.lastname: Clohessy
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fornari
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008938:Mitosis; D008954:Models, Biological; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse