Preproorexin and Orexin Receptors Are Expressed in Cortisol-Secreting Adrenocortical Adenomas, and Orexins Stimulate in Vitro Cortisol Secretion and Growth of Tumor Cells

• Published in: The journal of clinical endocrinology and metabolism 2005-06, Vol.90 (6), p.3544-3549
• Main Authors: Spinazzi, R., Rucinski, M., Neri, G., Malendowicz, L. K., Nussdorfer, G. G.
• Format: Article
• Language: English
• Subjects: Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - pathology; Adrenal Cortex Neoplasms - secretion; Adrenocortical Adenoma - genetics; Adrenocortical Adenoma - pathology; Adrenocortical Adenoma - secretion; Biological and medical sciences; DNA Primers; DNA, Complementary - genetics; Endocrinopathies; Fundamental and applied biological sciences. Psychology; Gene Amplification; Humans; Hydrocortisone - secretion; Intracellular Signaling Peptides and Proteins - pharmacology; Medical sciences; Neuropeptides - pharmacology; Orexin Receptors; Orexins; Polymerase Chain Reaction; Receptors, G-Protein-Coupled; Receptors, Neuropeptide - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2004-2385

Orexins A and B are hypothalamic peptides that originate from the proteolytic cleavage of preproorexin and act through two subtypes of receptors, named OX1-R and OX2-R. OX1-R almost exclusively binds orexin-A, whereas OX2-R is nonselective for both orexins. We previously found that orexin-A, via the OX1-R, stimulates cortisol secretion from dispersed human adrenocortical cells. In this study, we demonstrate that six of eight cortisol-secreting adenomas expressed preproorexin mRNA, and seven of 10 adenomas contained measurable amounts of orexin-A but not orexin-B. Normal adrenal cortexes neither expressed preproorexin nor contained orexins. All adenomas expressed OX1-R and OX2-R mRNAs, and real-time PCR showed that the expression of both receptors was up-regulated in adenomas, compared with normal adrenal cortex. Orexin-A concentration-dependently raised basal cortisol secretion from freshly dispersed normal and adenomatous cells, minimal and maximal effective concentrations being 10−10 and 10−8 m, and the peptide efficacy (percent increase elicited by 10−8 m orexin-A) was significantly higher in adenomas than in the normal adrenal cortex. Orexin-B was ineffective, thereby indicating that orexin secretagogue action is mediated by the OX1-R. In contrast, both orexins (10−8 m) raised the proliferative activity of cultured normal and adenomatous cells, suggesting that this effect is mediated by OX2-R or both receptor subtypes. Collectively, our findings allow us to conclude that the orexin system is overexpressed in cortisol-secreting adenomas and suggest that orexin-A may act as an autocrine-paracrine regulator of the secretory activity and growth of some of these adrenal tumors.