title: Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro.
abstract: The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.
authors.affiliation: Institute of Endocrinology and Metabolism and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gorshtein
authors.forename: Hadara
authors.initials: H
authors.lastname: Rubinfeld
authors.forename: Efrat
authors.initials: E
authors.lastname: Kendler
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.forename: Vesna
authors.initials: V
authors.lastname: Cerovac
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Zvi R
authors.initials: ZR
authors.lastname: Cohen
authors.forename: Moshe
authors.initials: M
authors.lastname: Hadani
authors.forename: Ilan
authors.initials: I
authors.lastname: Shimon
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D056743:Cyclin D3 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D050684:E2F Transcription Factors / Q000378:metabolism / Q000502:physiology; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C534696:CCND3 protein, human; D056743:Cyclin D3; D050684:E2F Transcription Factors; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus