ECE2015 Guided Posters Endocrine tumours and neoplasia – NETS (9 abstracts)
Filamin-A is involved in stabilisation, signal transduction, and angiogenesis regulation mediated by somatostatin receptor 2 in pancreatic neuroendocrine tumors
Eleonora Vitali 1 , Valeria Cambiaghi 1 , Federica Loiarro 1 , Alessandro Zerbi 2 , Piergiuseppe Colombo 3 , Anna Spada 4 , Giovanna Mantovani 4 , Erika Peverelli 4 , Carlo Carnaghi 5 & Andrea Lania 1,
1Laboratory of Cellular and Molecular Endocrinology, IRCCS Clinical and Research Institute Humanitas, Rozzano, Milan, Italy; 2Pancreas Surgery Unit, IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy; 3Department of Pathology, IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy; 4Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 5Medical Oncology and Hematology Unit, Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; 6Biometra Department, Neurosurgery Department, IRCCS Humanitas Clinical Institute, University of Milan, Rozzano, Milan, Italy.
Somatostatin receptor type 2 (SST2) is the main pharmacological target of long-acting somatostatin analogues (SSA) widely used in patients with pancreatic neuroendocrine tumours (P-NETs). A subset of patients is resistant to SSA, although the molecular mechanisms responsible for resistance are poorly understood. Several studies identified cytoskeleton protein interactions as determinant in receptor anchoring, expression and signalling. Since SST2 was recently demonstrated to associate to filamin A (FLNA), we investigated the role of this cytoskeleton protein in SST2 expression, signalling and angiogenesis in human P-NETs and in QGP1 cell lines. We found no correlation between FLNA and SST2 expression in P-NETs, confirming this, FLNA knockdown did not induce changes in SST2 levels in QGP1 cells. Conversely, a significant reduction in SST2 expression was observed in FLNA silenced cells after selective long term SST2 activation with BIM23120 (−49±17%, P<0.05 vs basal). To evaluate the role of FLNA on SST2 signalling, we analysed cyclin D1 expression, ERK1/2 phosphorylation, and cAMP accumulation. Interestingly, the reduction in cyclin D1 levels (−44±22%, P<0.05 vs basal) and ERK1/2 phosphorylation (−59±18%, P<0.05 vs basal) induced by SST2 agonist (BIM23120) was abolished in FLNA-silenced QGP1 cells. Similarly, BIM23120 inhibited forskolin-stimulated cAMP accumulation in cells transfected with negative control and this effect was abrogated in FLNA silenced cells. In addition, BIM23120 incubation induced a decrease in both VEGF expression (−31±7% in negative control transfected cells, P<0.001 vs untreated cells) and VEGF release into control cell supernatants (−39±24%, P<0.05 vs untreated cells) and these effects being completely abolished by FLNA silencing. In conclusion, these results demonstrate that FLNA is required for SST2 stabilisation, signalling and angiogenesis in tumoural pancreatic neuroendocrine cells, thus suggesting a possible role of this cytoskeleton protein in determining the different responsiveness to SSA observed in P-NET patients.
Disclosure: This work was supported by an AIRC (Associazione Italiana Ricerca Cancro – Milan) grant number KFR062-2 to Adrea Lania and by Ricerca Funds by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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