OR26-3 Expression of beta arrestins and G-protein coupled receptor kinase 2 in pituitary adenomas and their role in the regulation of response to somatostatin analogue treatment in patients with GH-secreting adenomas

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR26-Pituitary Tumorigenesis: Advances in Mechanism & Treatment
Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:45 AM
Room 130 (Moscone Center)
Federico Gatto*1, Richard Abraham Feelders1, Rob Van der Pas1, Fadime Dogan1, Peter van Koetsveld1, Aart-Jan van der Lelij1, Sebastian JCMM Neggers1, Wouter W. de Herder1, Steven W Lamberts1, Diego Ferone2 and Leo J Hofland1
1Erasmus MC, Rotterdam, Netherlands, 2Univ of Genova, Genova, Italy
Background  Recent studies highlighted the GRK type 2 (GRK2) as the kinase mainly involved in somatostatin receptor (SSTR) ligand-induced phosphorylation. Following GRK2 mediated phosphorylation, β-arrestins are recruited to the cell membrane, driving receptor desensitization and internalization processes. To our knowledge, the expression of these intracellular molecules has not yet been evaluated in pituitary adenomas. We hypothesize that over-or underrepresentation of these proteins may influence responsiveness to somatostatin analogue (SSA) treatment.
Methods We evaluated in a total of 41 pituitary adenoma samples (31 GH-secreting -GHomas, 6 Non-functioning -NFPAs, 4 Prolactinomas -PRLomas), the mRNA expression (by qRT-PCR) of multiple SSTRs, GRK2, β-arrestin1 and β-arrestin2. Mutual correlations between SSTRs and intracellular proteins were investigated. In the GHomas group, these data were correlated with the in vivo response to an acute octreotide test and tumor-derived cells were tested to evaluate GH secretion after SSA treatment. Moreover, the effect of SSA treatment on β-arrestin and GRK2 mRNA expression was investigated.
Results SSTR expression between adenoma types was in line with previously published data. The relative expression of the intracellular proteins was comparable in the three adenoma histotypes, with low β-arrestin1 levels detected.In more detail, β-arrestin1 expression was significantly lower in GHomas and PRLomas, compared to NFPAs (p=0.0011 and p=0.0095), whereas GRK2 was higher in PRLomas and NFPAs compared to GHomas (p=0.0025 and p=0.025). In the GHomas group, GRK2 expression was inversely correlated to β-arrestin1 (p=0.023) and positively correlated to β-arrestin2 (p<0.0001). SSA treatment did not affect GRK2 and β-arrestin mRNA expression.  Interestingly,  β-arrestin1 was significantly lower (p=0.019) in tumors responders to in vitro octreotide treatment (>50% GH reduction), whereas GRK2 and sst2 were significantly higher (p=0.041 and p=0.049). In line with these findings, β-arrestin 1 mRNA levels were inversely correlated with the in vivo response to an acute octreotide test (p=0.001), while GRK2 and sst2 expression were positively correlated (p=0.031 and p=0.010).
Conclusions For the first time we characterized β-arrestin and GRK2 mRNA expression in a representative number of pituitary adenomas. Besides membrane sst2 expression, β-arrestin1 and GRK2 seem to have a role in modulating GH secretion in response to SSA treatment

Disclosure: RAF: Clinical Researcher, Novartis Pharmaceuticals, Speaker, Novartis Pharmaceuticals. Nothing to Disclose: FG, RV, FD, PV, AJV, SJN, WWD, SWL, DF, LJH

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