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

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.

Kisspeptin-1 directly stimulates LH and GH secretion from goldfish pituitary cells in a Ca2+-dependent manner

“…In mammals, Kiss1R activation is coupled to multiple intracellular signal transduction pathways [5]. However, as with Kiss1 effects on GnRH neurons, Kiss1 actions on pituitary gonadotrophs, somatotrophs and adenomas all involve increases in [Ca 2+ ] i [13,17,20,21,23]. In the present study, gKiss1 elevates [Ca 2+ ] i in goldfish pars distalis cells in a nifedipine-sensitive manner.…”

“…We also examined the interactions of gKiss1 10 with the two native goldfish GnRHs, salmon (s)GnRH (goldfish GnRH-3) and chicken (c)GnRH-II (goldfish GnRH-2) [48,49], on LH and GH release; these two GnRHs have been shown to be physiological neuroendocrine stimulators of both LH and GH secretion in this system [4,8,9]. Since Ca 2+ signalling and Ca 2+ entry through voltage-sensitive Ca 2+ channels (VSCCs) are important intracellular events in the neuroendocrine regulation of LH and GH release in goldfish [4,[7][8][9], and Ca 2+ mediates the actions of Kiss1 in many mammalian target tissues [23,28], we also tested the hypothesis that the hormone-releasing effects of gKiss1 10 are dependent on Ca 2+ entry via VSCCs.…”

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

“…Tissues were collected following the guidelines of the local committee on human research and immediately minced in RPMI-1640 medium (Invitrogen) under sterile conditions. Primary cultures were then prepared as described previously (Zatelli et al 2006, Martínez-Fuentes et al 2011. Informed consent of the patients was obtained for disclosing clinical investigation and performing the in vitro study.…”

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

“…32 Since KP peptides are known to modify tumor cell behavior, 44,45 we tested the effects of KP 42−54 and KP 45−50 on the toxicity of Aβ 1−42 and PrP 106−126 in rat cortical neuron primary cell cultures. 32,33 The results showed that KP 42−54 and KP 45−50 caused a dose-dependent inhibition of 5 μM Aβ 1−42 toxicity, which was significant at concentrations above 2.5 μM ( Figure 3A).…”