Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: Evidence for apoptotic action of kisspeptin-10

Antonio J. Martínez-Fuentes, Marcelo Molina, Rafael Vázquez-Martínez, Manuel D. Gahete, Luis Jiménez-Reina, Jesús Moreno-Fernández, Pedro Benito-López, Ana Quintero, Andrés De La Riva, Carlos Diéguez, Alfonso Soto, Alfonso Leal-Cerro, Eugenia Resmini, Susan M. Webb, Maria C. Zatelli, Ettore C. Degli Uberti, María M. Malagón, Raul M. Luque, Justo P. Castaño

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

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 [Ca2+]i in individual cells from four out of the five GH-producing adenomas studied, whereas cells derived from non-functioning pituitary adenomas (NFPA, n=45) 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. © 2011 European Society of Endocrinology.
Original languageEnglish
Pages (from-to)355-362
JournalEuropean Journal of Endocrinology
Volume164
DOIs
Publication statusPublished - 1 Mar 2011

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