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

• Published in: The journal of clinical endocrinology and metabolism Vol. 93; no. 6; pp. 2269 - 2276
• Main Authors: Vazquez-Martinez, Rafael, Martinez-Fuentes, Antonio J, Pulido, Marina R, Jimenez-Reina, Luis, Quintero, Ana, Leal-Cerro, Alfonso, Soto, Alfonso, Webb, Susan M, Sucunza, Nuria, Bartumeus, Frederic, Benito-Lopez, Pedro, Galvez-Moreno, Maria A, Castaño, Justo P, Malagon, Maria M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.06.2008; Copyright by The Endocrine Society
• Subjects: Acromegaly - etiology; Acromegaly - genetics; Adenoma - genetics; Adenoma - metabolism; Adenoma - secretion; Biological and medical sciences; Cell Membrane - metabolism; Endocrinopathies; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - physiology; Growth Hormone-Secreting Pituitary Adenoma - genetics; Growth Hormone-Secreting Pituitary Adenoma - metabolism; Growth Hormone-Secreting Pituitary Adenoma - secretion; Human Growth Hormone - secretion; Humans; Hypothalamus. Hypophysis. Epiphysis (diseases); Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; rab GTP-Binding Proteins - physiology; RNA, Messenger - metabolism; Secretory Vesicles - metabolism; Somatotrophs - metabolism; Somatotrophs - secretion; Tissue Distribution; Transfection; Tumor Cells, Cultured; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Obesity; Endocrine gland; Nutrition; Diseases of the osteoarticular system; Nutrition disorder; Acromegaly; Gene overexpression; Metabolic diseases; Hypersecretion; Somatotropin; Reduction; Adenohypophyseal hormone; Pituitary diseases; Pituitary gland; Tumor; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2007-1893

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.