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Ghrelin receptor (GHS-R1a) and its constitutive activity in somatotroph adenomas: a new co-targeting therapy using GHS-R1a inverse agonists and somatostatin analogs. | LitMetric

Ghrelin receptor (GHS-R1a) and its constitutive activity in somatotroph adenomas: a new co-targeting therapy using GHS-R1a inverse agonists and somatostatin analogs.

J Clin Endocrinol Metab

Aix-Marseille University (Y.M., M.-P.B., C.D., T.B., T.G., A.B., A.E., S.T.), Centre National de la Recherche Scientifique, CRN2M UMR7286, 13344 Marseille, France; APHM, Conception (A.B., A.E.), Laboratory of Molecular Biology, 13385 Marseille, France; APHM, Timone, Department of Endocrinology (T.B.), Department of Neurosurgery (T.G.), and Laboratory of Neuropathology (D.F.-B.), 13385 Marseille, France; Aix-Marseille University (D.F.-B.), INSERM, CRO2 UMR911, 13385 Marseille, France; and Buenos Aires University (M.M.), Department of Endocrinology, Hospital de Clinicas, Buenos Aires 1120, Argentina.

Published: December 2014

AI Article Synopsis

Article Abstract

Context: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature.

Objective: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target.

Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied.

Results: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs.

Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.

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Source
http://dx.doi.org/10.1210/jc.2014-2753DOI Listing

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