Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro

• Published in: Endocrine-related cancer Vol. 16; no. 3; pp. 1017 - 1027
• Main Authors: Gorshtein, Alexander, Rubinfeld, Hadara, Kendler, Efrat, Theodoropoulou, Marily, Cerovac, Vesna, Stalla, Günter K, Cohen, Zvi R, Hadani, Moshe, Shimon, Ilan
• Format: Journal Article
• Language: English
• Published: England Society for Endocrinology 01.09.2009; BioScientifica
• Subjects: Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Antineoplastic Agents - pharmacology; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclin D3 - metabolism; Drug Evaluation, Preclinical; E2F Transcription Factors - metabolism; E2F Transcription Factors - physiology; Everolimus; Gene Expression Regulation, Neoplastic - drug effects; Growth Hormone-Secreting Pituitary Adenoma - genetics; Growth Hormone-Secreting Pituitary Adenoma - metabolism; Growth Hormone-Secreting Pituitary Adenoma - pathology; Humans; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Regular papers; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; TOR Serine-Threonine Kinases; Tumor Cells, Cultured
• ISSN: 1351-0088; 1479-6821
• DOI: 10.1677/ERC-08-0269

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.