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 disregulated secretory activities.

Objective: Herein, we have 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 (9 patients) or with non-functioning adenomas (9 patients) underwent endoscopic trans-sphenoidal 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 to cells from non-functioning pituitary adenomas (NFPA) derived from patients with normal or reduced GH plasma levels (100%). Furthermore, immunoelectron microscopy revealed that Rab18 association to the surface of GH-containing secretory granules was significantly lower in somatotropes from acromegalies than from NFPA. Finally, we provide evidence that modulation of Rab18 gene expression can revert substantially the hypersecretory activity of cells, as 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.