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Rab18 Is Reduced in Pituitary Tumors Causing Acromegaly and Its Overexpression Reverts Growth Hormone Hypersecretion

Department of Cell Biology, Physiology, and Immunology (R.V.-M., A.J.M.-F., M.R.P., A.Q., J.P.C., M.M.M.), University of Cordoba, Centros de Investigacion Biomedica en Red (CIBER) Obesidad y Nutricion (R.V.-M., A.J.M.-F., M.R.P., A.Q., J.P.C., M.M.M.), Instituto Carlos III, and Department of Morphological Sciences (L.J.-R.), University of Cordoba, E-14014, Cordoba, Spain; Division of Endocrinology (A.L.-C., A.S.), Virgen del Rocio University Hospital, E-41013 Sevilla, Spain; Department of Endocrinology (S.M.W., N.S.), Center for Biomedical Research on Rare Diseases (CIBER U747), and Service of Neurosurgery (F.B.), Sant Pau Hospital, Autonomous University of Barcelona, E-08025 Barcelona, Spain; and Service of Endocrinology and Nutrition (P.B.-L., M.A.G.-M.), Reina Sofia Hospital, E-14004 Cordoba, Spain

Address all correspondence and requests for reprints to: Maria M. Malagon, Ph.D., Department of Cell Biology, Physiology, and Immunology, Campus de Rabanales. Edificio Severo Ochoa. Pl. 3., University of Cordoba, E-14014 Cordoba, Spain. E-mail: bc1mapom{at}uco.es.

Context: Rab proteins regulate the sequential steps of intracellular membrane transport. Alterations of these GTPases and their associated proteins are emerging as the underlying cause for several human diseases involving dysregulated secretory activities.

Objective: Herein we investigated the role of Rab18, which negatively regulates hormone secretion by interacting with secretory granules, in relation to the altered functioning of tumoral pituitary somatotropes causing acromegaly.

Patients: A total of 18 patients diagnosed with pituitary tumors causing acromegaly (nine patients) or nonfunctioning adenomas (nine patients) underwent endoscopic transsphenoidal surgery. Adenomas were subsequently processed to evaluate Rab18 production in relation to GH secretion.

Results: We found that somatotropinoma cells are characterized by a high secretory activity concomitantly with a remarkably reduced Rab18 expression (15%) and protein content levels (30%), as compared with cells from nonfunctioning pituitary adenomas derived from patients with normal or reduced GH plasma levels (100%). Furthermore, immunoelectron microscopy revealed that Rab18 association with the surface of GH-containing secretory granules was significantly lower in somatotropes from acromegalies than nonfunctioning pituitary adenomas. Finally, we provide evidence that modulation of Rab18 gene expression can revert substantially the hypersecretory activity of cells because Rab18 overexpression reduced by 40% the capacity of cells from acromegalies to respond to GHRH stimulation.

Conclusion: These results suggest that molecular alterations affecting individual components of the secretory granule traffic machinery can contribute to maintain a high level of GH in plasma. Accordingly, Rab18 constitutes a valuable target as a diagnostic, prognostic, and/or therapeutic tool for human acromegaly.