The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells.
Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K-induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)-mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser(473)-phosphorylated Akt (pAkt-Ser(473)) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser(473) through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G(1) cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin.
Cerovac
Vesna
V
Department of Endocrinology, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Monteserin-Garcia
Jose
J
Rubinfeld
Hadara
H
Buchfelder
Michael
M
Losa
Marco
M
Florio
Tullio
T
Paez-Pereda
Marcelo
M
Stalla
Günter K
GK
Theodoropoulou
Marily
M
D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D015282:Octreotide / Q000008:administration & dosage / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015854:Up-Regulation
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051058:Oncogene Protein v-akt; D015282:Octreotide; D020123:Sirolimus