Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro.
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.
Gorshtein
Alexander
A
Institute of Endocrinology and Metabolism and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel.
Rubinfeld
Hadara
H
Kendler
Efrat
E
Theodoropoulou
Marily
M
Cerovac
Vesna
V
Stalla
Günter K
GK
Cohen
Zvi R
ZR
Hadani
Moshe
M
Shimon
Ilan
I
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
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