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Sci. Signal., 27 January 2009
Vol. 2, Issue 55, p. ra2
[DOI: 10.1126/scisignal.2000189]

RESEARCH ARTICLES

Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis

Caterina Nardella1, Arkaitz Carracedo1*, Andrea Alimonti1*, Robin M. Hobbs1, John G. Clohessy1, Zhenbang Chen1, Ainara Egia1, Alessandro Fornari2,3, Michelangelo Fiorentino2, Massimo Loda2,4, Sara C. Kozma5, George Thomas5, Carlos Cordon-Cardo6, and Pier Paolo Pandolfi1{dagger}

1 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3 Department of Biomedical Sciences and Human Oncology, Molinette Hospital, University of Turin, 10126 Turin, Italy.
4 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
5 Department of Genome Science, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
6 Department of Pathology, Columbia University, New York, NY 10032, USA.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: ppandolf{at}bidmc.harvard.edu

Citation: C. Nardella, A. Carracedo, A. Alimonti, R. M. Hobbs, J. G. Clohessy, Z. Chen, A. Egia, A. Fornari, M. Fiorentino, M. Loda, S. C. Kozma, G. Thomas, C. Cordon-Cardo, P. P. Pandolfi, Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis. Sci. Signal. 2, ra2 (2009).

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