CLINICAL STUDY Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10 Antonio J Martı ´nez-Fuentes 1 , Marcelo Molina 1 , Rafael Va ´zquez-Martı ´nez 1 , Manuel D Gahete 1 , Luis Jime ´nez- Reina 2 , Jesu ´ s Moreno-Ferna ´ndez 3 , Pedro Benito-Lo ´pez 3 , Ana Quintero 1 , Andre ´s de la Riva 4 , Carlos Die ´guez 5 , Alfonso Soto 6 , Alfonso Leal-Cerro 6 , Eugenia Resmini 7 , Susan M Webb 7 , Maria C Zatelli 8 , Ettore C degli Uberti 8 , Marı ´a M Malago ´n 1 , Raul M Luque 1 and Justo P Castan ˜o 1 1 Department of Cell Biology, Physiology and Immunology, Instituto Maimo ´nides de Investigacio ´n Biome ´dica de Co ´rdoba (IMIBIC), and CIBER Fisiopatologı ´a de la Obesidad y Nutricio ´n (CIBERobn) and 2 Department of Morphological Sciences, University of Co ´rdoba, Edificio Severo Ochoa, Planta 3, Campus de Rabanales, E-14014 Co ´rdoba, Spain, 3 Service of Endocrinology and Nutrition and 4 Service of Neurosurgery, Hospital Reina Sofı ´a, Co ´rdoba, Spain, 5 Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain, 6 Division of Endocrinology, Virgen del Rocio University Hospital, Sevilla, Spain, 7 Endocrinology and Medicine Departments and Centro de Investigacio ´n Biome ´dica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Hospital Sant Pau, Universitat Auto `noma de Barcelona, Barcelona, Spain and 8 Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, Universityof Ferrara, Ferrara, Italy (Correspondence should be addressed to J P Castan ˜o; Email: justo@uco.es) Abstract Context: KISS1 was originally identified as a metastasis-suppressor gene able to inhibit tumor progression. KISS1 gene products, the kisspeptins, bind to a G-protein-coupled receptor (KISS1R, formerly GPR54), which is highly expressed in placenta, pituitary, and pancreas, whereas KISS1 mRNA is mainly expressed in placenta, hypothalamus, striatum, and pituitary. Objective and design: KISS1/KISS1R pituitary expression profile, coupled to their anti-tumoral capacities, led us to hypothesize that this system may be involved in the biology of pituitary tumors. To explore this notion, expression levels of KISS1R and KISS1 were evaluated in normal and adenomatous pituitaries. Additionally, functionality of this system was assessed by treating dispersed pituitary adenoma cells in primary culture with kisspeptin-10 and evaluating intracellular calcium kinetics and apoptotic rate. Results: Both KISS1 and KISS1R were expressed in normal pituitary, whereas this simultaneous expression was frequently lost in pituitary tumors, where diverse patterns of KISS1/KISS1R expression were observed that differed among distinct types of pituitary adenomas. Measurement of calcium kinetics revealed that kisspeptin-10 elicits a remarkable increase in [Ca 2C ] i in individual cells from four out of the five GH-producing adenomas studied, whereas cells derived from non-functioning pituitary adenomas (NFPA, nZ45) did not respond. In contrast, kisspeptin-10 treatment increased the apoptotic rate in cells derived from both GH-producing and NFPA. Conclusions: These results provide primary evidence that KISS1 and KISS1R expression can be differentially lost in pituitary tumor subtypes, where this system can exert functional, proapoptotic actions, and thereby offer novel insights to investigate the biology and therapeutic options to treat these tumors. European Journal of Endocrinology 164 355–362 Introduction Pituitary adenomas are relatively rare, regularly benign neoplasms, which exhibit a wide range of biological behaviors in terms of hormone production and cell proliferation, and ultimately result from health compli- cations (1). In most instances, early surgical interven- tion provides the best chance for either the cure or the control of pituitary tumor progression and its side effects (2). To date, medical strategies are strongly dependent on the specific tumor, and the options are limited by the reduced number of effective molecular targets that can be employed. Accordingly, it is of high interest to identify and characterize new molecules that could serve as potential targets for pituitary tumor treatment. The KISS1 gene encodes a precursor protein that is processed into several related peptides, generically named kisspeptins (3–5), where the major product appears to be a 54-amino acid peptide, named kisspeptin-54 or metastin. In addition, three natural European Journal of Endocrinology (2011) 164 355–362 ISSN 0804-4643 q 2011 European Society of Endocrinology DOI: 10.1530/EJE-10-0905 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 05/22/2020 12:38:52PM via free access