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Lee, M.S. ; Theodoropoulou, M.* ; Graw, J. ; Roncaroli, F.* ; Zatelli, M.C.* ; Pellegata, N.S.

Levels of p27 sensitize to dual PI3K/mTOR inhibition.

Mol. Cancer Ther. 10, 1450-1459 (2011)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling cascade occurs in a variety of human malignancies, where it sustains tumor cell proliferation and survival. Pharmacologic blockade of this pathway exerts antineoplastic activity by triggering apoptosis and/or cell-cycle arrest. Pituitary adenomas show activation of the PI3K/AKT/mTOR pathway, but only a fraction of them respond in vitro to the antiproliferative action of rapamycin and RAD001 (mTOR inhibitors), possibly because of the described negative feedback loop on AKT which reactivates the signaling cascade. Rats affected by the multiple endocrine neoplasia-like syndrome (MENX) develop pituitary adenomas showing increased activated AKT. In this study, we comparatively investigated the antitumor potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235 and the single mTOR inhibitor RAD001 on rat pituitary adenoma cells in primary culture. NVP-BEZ235 inhibits the PI3K pathway both upstream and downstream of AKT, thereby preventing the negative feedback loop. NVP-BEZ235 was more effective than RAD001 in reducing cell viability of pituitary adenomas. Consistently, NVP-BEZ235 treatment decreased Akt and S6 phosphorylation and triggered apoptosis. Because MENX is caused by a germline loss-of-function mutation in the cell-cycle inhibitor p27Kip1, we investigated the relationship between this defect and response to NVP-BEZ235 treatment. The levels of p27Kip1 positively correlate with the response to NVP-BEZ235 treatment. Combined treatment with NVP-BEZ235 and the proteasome inhibitor bortezomib, which increases p27Kip1 amount, shows synergistic antiproliferative effects on pituitary adenoma cells. Our data suggest that NVP-BEZ235 may represent an effective therapeutic modality for pituitary adenomas and that p27Kip1 levels represent a potential predictor of response to dual PI3K/mTOR inhibition.
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Publication type Article: Journal article
Document type Scientific Article
Keywords phosphatidylinositol 3-kinase/mammalian target; nonfunctioning pituitary-adenomas; rapamycin inhibitor; breast-cancer; tumor-cells; prolactin secretion; dopamine agonists; p27(kip1) protein; mammalian target; nvp-bez235
Language english
Publication Year 2011
HGF-reported in Year 2011
ISSN (print) / ISBN 1535-7163
e-ISSN 1538-8514
Journal Molecular Cancer Therapeutics
Quellenangaben Volume: 10, Issue: 8, Pages: 1450-1459 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, PA , USA
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
Institute of Developmental Genetics (IDG)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30204 - Cell Programming and Repair
Research field(s) Enabling and Novel Technologies
Genetics and Epidemiology
PSP Element(s) G-500300-001
G-500500-002
PubMed ID 21646547
DOI 10.1158/1535-7163.MCT-11-0188
Scopus ID 80051598688
Erfassungsdatum 2011-11-10
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