title: Effects of AMPK activation and combined treatment with AMPK activators and somatostatin on hormone secretion and cell growth in cultured GH-secreting pituitary tumor cells.
abstract: We investigated the effects of the AMPK activator AICAR as compared to somatostatin-14 on cell viability and GH secretion in human GH-secreting pituitary adenomas in vitro and in rat GH3 cells. Overnight treatment with AICAR increased phospho-(threonine-172) AMPK levels (activated AMPK) in cultured human adenomas. As to the effects on cell viability, four adenomas out of 15 were responsive to AICAR (0.4mM) and five adenomas were responsive to SS-14 (100 nM). One adenoma was responsive to both somatostatin and AICAR. The effects of cotreatment with SS-14 and AICAR were investigated in eight adenomas. In two adenomas, the effects of AICAR+SS-14 did not exceed the effect of AICAR. In two adenomas which were not responsive to either AICAR or SS-14, the cotreatment was able to reduce cell viability versus control. Two adenomas were not responsive to any treatment. As to the effects on GH secretion, nine adenomas out of 15 were responsive to AICAR. Twelve adenomas were responsive to SS-14. Eight adenomas were responsive to both AICAR and SS-14. Cotreatment exceeded the effect of single treatments in 4 out of 10 adenomas. In GH3 cells, AICAR reduced the activity of p70S6 kinase, which plays an important role in cell growth. SS-14 did not affect significantly AMPK phosphorylation and p70S6K activity but it was able to enhance the inhibitory effect of AICAR on phospho-S6 levels. Moreover, AICAR and SS-14 reduced ERK phosphorylation with a different time course. The combined treatment reduced phospho-ERK levels at any time point.
authors.affiliation: Pharmacology Unit, Department of Biomedical Sciences and Biotechnologies, University of Brescia, Italy. tulipano@med.unibs.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tulipano
authors.forename: Lara
authors.initials: L
authors.lastname: Faggi
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.forename: Pietro
authors.initials: P
authors.lastname: Mortini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Spinello
authors.forename: Valeria
authors.initials: V
authors.lastname: Sibilia
authors.forename: Francesca
authors.initials: F
authors.lastname: Pagani
authors.forename: Daniela
authors.initials: D
authors.lastname: Cocchi
authors.forename: Andrea
authors.initials: A
authors.lastname: Giustina
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism*; D000328:Adult; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology*; D013004:Somatostatin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D012265:Ribonucleotides; D019382:Human Growth Hormone; D000620:Aminoimidazole Carboxamide; D013004:Somatostatin; D048049:Extracellular Signal-Regulated MAP Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide