title: Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10.
abstract: BACKGROUND
  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
  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(2+)](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.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), University of Córdoba, Córdoba, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Martínez-Fuentes
authors.forename: Marcelo
authors.initials: M
authors.lastname: Molina
authors.forename: Rafael
authors.initials: R
authors.lastname: Vázquez-Martínez
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.forename: Luis
authors.initials: L
authors.lastname: Jiménez-Reina
authors.forename: Jesús
authors.initials: J
authors.lastname: Moreno-Fernández
authors.forename: Pedro
authors.initials: P
authors.lastname: Benito-López
authors.forename: Ana
authors.initials: A
authors.lastname: Quintero
authors.forename: Andrés
authors.initials: A
authors.lastname: de la Riva
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Alfonso
authors.initials: A
authors.lastname: Soto
authors.forename: Alfonso
authors.initials: A
authors.lastname: Leal-Cerro
authors.forename: Eugenia
authors.initials: E
authors.lastname: Resmini
authors.forename: Susan M
authors.initials: SM
authors.lastname: Webb
authors.forename: Maria C
authors.initials: MC
authors.lastname: Zatelli
authors.forename: Ettore C
authors.initials: EC
authors.lastname: degli Uberti
authors.forename: María M
authors.initials: MM
authors.lastname: Malagón
authors.forename: Raul M
authors.initials: RM
authors.lastname: Luque
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D059648:Kisspeptins; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D025521:Tumor Suppressor Proteins; D002118:Calcium