Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly

European Journal of Endocrinology - Tập 174 Số 5 - Trang 651-662 - 2016
Federico Gatto1, Nienke R. Biermasz2, Richard A. Feelders1,3, Johan M. Kros4,3, Fadime Dogan1, A. J. van der Lely1,3, Sebastian Neggers1,3, Steven W. J. Lamberts1, Alberto M. Pereira2, Diego Ferone5, Leo J. Hofland1,3
1Department of Internal Medicine, Division Endocrinology, Erasmus MC, Rotterdam, The Netherlands
2Department of Medicine, Division of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The Netherlands
3Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
4Pathology, Erasmus MC, Rotterdam, The Netherlands
5Endocrinology, Department of Internal Medicine and Medical Specialties (DIMI) and Center of Excellence for Biomedical Research (CEBR), IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy

Tóm tắt

AbstractObjectiveThe high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function.DesignTo investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands.Methodsβ-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients.Resultsβ-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P= 0.024 andP= 0.047) and complete biochemical control (P= 0.047 andP= 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P= 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P= 0.011 andP= 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P= 0.045 andP= 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ= –0.69,P= 0.0011 andρ= –0.67,P= 0.0016).ConclusionsLow β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.

Từ khóa


Tài liệu tham khảo

10.1056/NEJMra062453

10.1210/jc.2006-1668

10.1111/j.1365-2265.2009.03667.x

10.1210/jc.2010-0537

10.1038/nrendo.2014.21

Gadelha, 2013, Novel pathway for somatostatin analogs in patients with acromegaly, Trends in Endocrinology & Metabolism, 24, 238, 10.1016/j.tem.2012.11.007

Carmichael, 2014, Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis, Journal of Clinical Endocrinology & Metabolism, 99, 1825, 10.1210/jc.2013-3757

10.1210/jc.2007-1986

Fougner, 2008, The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma, Clinical Endocrinology, 68, 458, 10.1111/j.1365-2265.2007.03065.x

10.1210/jc.2012-2609

Wildemberg, 2013, Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs, Journal of Endocrinological Investigation, 36, 38

10.1530/JME-14-0011

10.1530/EJE-07-0562

10.1210/jc.2009-2247

10.1210/jc.2009-2556

10.1002/ijc.24602

10.1210/jc.2009-2197

10.1210/jc.2007-2272

10.1074/jbc.M313522200

10.1016/j.tips.2011.05.002

10.1210/en.2013-1672

10.1210/en.2008-0244

10.1210/jc.2003-031344

10.1210/jc.2008-2101

10.1210/jc.2013-1987

10.1159/000329876

10.1007/s11102-009-0191-1

10.1210/er.2010-0002

10.1210/jc.85.2.781

10.1530/eje.1.02313

Attramadal, 1992, Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family, Journal of Biological Chemistry, 267, 17882, 10.1016/S0021-9258(19)37125-X

10.1073/pnas.98.4.1601

10.1073/pnas.1209411109

10.1074/jbc.M910348199

10.1074/jbc.275.17.12900

10.1016/S0014-5793(02)02517-6

10.1124/mol.107.038570

Liu, 2005, Receptor signaling and endocytosis are differentially regulated by somatostatin analogs, Molecular Pharmacology, 68, 90, 10.1124/mol.105.011767

10.1210/jc.2013-2145

10.1530/eje.1.02354

10.1016/j.tips.2013.10.001

10.1530/JME-11-0121

Shenoy, 2011, beta-arrestin-biased signaling by the beta-adrenergic receptors, Advances in Adrenergic Receptor Biology, 67, 51

10.1210/me.2009-0321

Thông tin
Thông tin xuất bản

European Journal of Endocrinology

Tập 174 Số 5

651-662

Thông tin tác giả