ECE2017 Eposter Presentations: Pituitary and Neuroendocrinology Pituitary - Basic (13 abstracts)
SSTR2 inhibits GH-secreting pituitary tumoral cells migration and invasion by increasing cofilin phosphorylation
Erika Peverelli 1 , Elena Giardino 1 , Donatella Treppiedi 1 , Marco Locatelli 2 , Andrea G Lania 3 , Maura Arosio 1 , Anna Spada 1 & Giovanna Mantovani 1
1Endocrine Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 2Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 3Endocrine Unit, IRCCS Humanitas Clinical Institute, Humanitas University, Rozzano, Italy.
Although generally benign, pituitary tumors frequently present local invasiveness that strongly reduces neurosurgery success. We recently demonstrated a role for the actin binding protein cofilin in promoting non functioning pituitary tumors invasiveness and an inhibitory effect of dopamine receptor type 2. Somatostatin (SS) receptor type 2 (SSTR2) is the main target of pharmacological therapy of GH-secreting pituitary tumors, reducing both GH secretion and cell proliferation, but its effects on cell invasion have never been investigated. Aims of this study were: i) to evaluate the effects of SSTR2 agonist on migration and invasion of rat somatomammotroph GH3 cells and human GH-secreting pituitary tumoral cells, and ii) to investigate the molecular mechanisms focusing on the role of cofilin and the cytoskeleton protein FLNA, that directly interacts with SSTR2. Our data demonstrated that SSTR2 agonist BIM23120 incubation significantly reduced migration (31.3%±12.2%, P<0.01) and invasion on collagen IV (22%±3.6%, P<0.001) of GH3, these data being replicated in human GH-secreting tumoral cells (14±2.9% and 41.7±11.3% reduction of cell migration and invasion, respectively, P<0.05). Moreover, BIM23120 induced a marked increase of phosphorylated (inactive) cofilin in both GH3 and primary tumoral pituitary cells (about 2.7 and 2.1-fold over basal, respectively). This effect was completely abolished by specific ROCK inhibitor Y27632 but not by pertussis toxin, suggesting an involvement of Rho/ROCK/LIMK pathway and excluding a role for inhibitory heterotrimeric G proteins. Co-immunoprecipitation experiments revealed an association of SSTR2 with FLNA, cofilin and LIMK1, suggesting a role for FLNA as scaffold protein mediating SS effects on cofilin pathway. In conclusion, our data revealed an inhibitory effect of SSTR2 on GH-secreting pituitary tumor cells migration and invasion involving ROCK-dependent phosphorylation of cofilin.
Volume 49
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