Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment

Dhillo, Waljit S.; Savage, Philip; Murphy, Kevin G.; Chaudhri, Owais B.; Patterson, Michael; Nijher, Gurjinder; Foggo, Vanessa M; Dancey, G; Mitchell, Hugh D.; Seckl, Michael J.; Ghatei, Mohammed A.; Bloom, Stephen R.

doi:10.1152/ajpendo.00555.2005

Cited by 68 publications

(66 citation statements)

References 42 publications

(67 reference statements)

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“…The relatively prolonged effects of kisspeptin on insulin secretion in vivo and in vitro is in accordance with previous studies demonstrating sustained effects of kisspeptin in the hypothalamus for over 1 h after administration [15,34]. Measurements using a commercially available assay suggested that the intravenous administration schedule used in our in vivo experiments produced increases in plasma kisspeptin (9 nmol/l) of the same order of magnitude as the physiological increases (2.5 nmol/l) reported in pregnant women [19], suggesting that there are circumstances where circulating kisspeptin could influence islet function. However, some caution is required in interpreting these data, since plasma kisspeptin can be difficult to measure accurately [35].…”

Section: Discussionsupporting

confidence: 92%

“…Little information is yet available about the biologically active concentrations of kisspeptin, and there are at least two possible sources of kisspeptin that may activate the beta cell GPR-54. Circulating levels of kisspeptin in humans are normally very low but increase markedly during pregnancy, and this circulating kisspeptin is assumed to be of placental origin [19]. Peak kisspeptin concentrations of approximately 2.5 nmol/l are detected during the third trimester in humans [19], but this is still somewhat lower than the concentrations of approximately 50 nmol/l that were required to stimulate insulin secretion from mouse islets in our in vitro experiments.…”

Section: Discussionmentioning

confidence: 53%

“…Circulating levels of kisspeptin in humans are normally very low but increase markedly during pregnancy, and this circulating kisspeptin is assumed to be of placental origin [19]. Peak kisspeptin concentrations of approximately 2.5 nmol/l are detected during the third trimester in humans [19], but this is still somewhat lower than the concentrations of approximately 50 nmol/l that were required to stimulate insulin secretion from mouse islets in our in vitro experiments. To date there is no information about placental production or circulating levels of kisspeptin in mice, so it is possible that plasma kisspeptin levels during pregnancy reach higher levels in mice with their multiple placentas.…”

Section: Discussionmentioning

confidence: 53%

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Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats

et al. 2009

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Aims/hypothesis Kisspeptin is a novel peptide identified as an endogenous ligand of the G-protein-coupled receptor 54 (GPR-54), which plays a crucial role in puberty and reproductive function. High levels of GPR-54 and kisspeptin have been reported in the pancreas and we have previously shown that kisspeptin potentiates glucose-induced insulin release from isolated islets, although the mechanisms underlying this effect were unclear. Methods Insulin secretion from isolated mouse islets was measured to characterise the effects of kisspeptin. The effects of kisspeptin on both p42/44 mitogen-activated protein kinase (MAPK) phosphorylation and intracellular Ca 2+ ([Ca 2+ ] i ) in mouse islets were also investigated. Furthermore, kisspeptin was administered to rats in vivo and effects on plasma insulin levels measured. Results In the current study, kisspeptin induced a concentration-dependent potentiation of glucose-induced (20 mmol/l) insulin secretion from mouse islets, with maximal effects at 1 µmol/l, but had no effect on insulin secretion at a substimulatory concentration of glucose (2 mmol/l). Activation of GPR-54 by kisspeptin also caused reversible increases in [Ca 2+ ] i in Fura-2 loaded dispersed islet cells.The kisspeptin-induced potentiation of glucose-induced insulin secretion was completely abolished by inhibitors of phospholipase C and p42/44 MAPK, but not by inhibitors of protein kinase C or p38 MAPK. Intravenous administration of kisspeptin into conscious, unrestrained rats caused an increase in circulating insulin levels, whilst central administration of kisspeptin had no effect, indicating a peripheral site of action. Conclusions/interpretation These observations suggest that neither typical protein kinase C isoforms nor p38 MAPK are involved in the potentiation of glucose-induced insulin release by kisspeptin, but intracellular signalling pathways involving phospholipase C, p42/44 MAPK and increased [Ca 2+ ] i are required for the stimulatory effects on insulin secretion. The observation that kisspeptin is also capable of stimulating insulin release in vivo supports the conclusion that kisspeptin is a regulator of beta cell function.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 53%

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Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats

et al. 2009

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“…Cells were allowed to grow to confluence and serum starved in RPMI-1640 medium with 100 IU/ml penicillin and 100 μg/ml streptomycin (serum-free medium, SFM) for 2 h. In order to investigate the time course of kisspeptin release from human prostate cancer cell lines, 500 μl/well fresh SFM was then added (T=0). Cells were incubated at 37˚C and medium was collected at T=2, 4 or 24 h (n=4 wells/group) and stored at -20˚C until measurement of kisspeptin immunoreactivity (-IR) using an established radioimmunoassay (RIA) (32,(35)(36)(37). The RIA antibody cross-reacted 100% with human kisspeptin-54, kisspeptin-14, and kisspeptin-10 and <0.01% with other related RF amide proteins, including prolactin-releasing peptide, RF amiderelated peptide 1 (RFRP1), RFRP2, RFRP3, QRFP43, neuropeptide FF, and neuropeptide AF.…”

Section: Kisspeptin Release By Human Prostate Cancer Cell Linesmentioning

confidence: 99%

“…Kisspeptin was originally known as metastin because it was implicated in suppression of tumour metastasis in a number of human cancers (22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and circulating kisspeptin has been proposed as a tumour marker for gestational trophoblastic disease and pancreatic cancer (32,33). However, the levels of kisspeptin in prostatic cancer have not previously been investigated.…”

Section: Introductionmentioning

confidence: 99%

Kisspeptin is released from human prostate cancer cell lines but plasma kisspeptin is not elevated in patients with prostate cancer

Curtis

Murphy²,

Chaudhri³

et al. 2010

Oncol Rep

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Abstract. Kisspeptin, the product of the KiSS-1 gene, inhibits metastasis and stimulates the hypothalamo-pituitarygonadal axis. Kisspeptin is therefore a putative target in the treatment of hormone-sensitive malignancies. Prostatic carcinoma remains a significant cause of mortality despite improvements in therapy. The role of kisspeptin in prostatic carcinoma remains undefined. We therefore aimed to investigate release of kisspeptin by prostatic cancer cell lines; investigate expression of KiSS-1 in human prostate tissue; investigate whether patients with prostate carcinoma have elevated plasma kisspeptin. 1) Culture medium from prostatic carcinoma cell lines LNCaP, DU145 and PC3 was assayed for kisspeptin immunoreactivity (-IR). Kisspeptin-IR release was detectable from all three cell lines. The effect of hydroxyflutamide, gefitinib and resveratrol on kisspeptin-IR release from these cell lines was also investigated. No effect of the drugs tested on release of kisspeptin-IR was observed. 2) Expression of KiSS-1 in human prostate tissue (n=4) was investigated using in situ hybridisation. Expression of KiSS-1 was detected in human prostate tissue. 3) Plasma kisspeptin-IR was compared in 92 patients with prostatic carcinoma and 73 male controls. Kisspeptin-IR was not detected in the plasma of either patients with prostate cancer or control patients. We have therefore shown for the first time the release of kisspeptin-IR by prostatic carcinoma cell lines. We have also shown that KiSS-1 is expressed in human prostate tissue, and that circulating levels of kisspeptin-IR are not elevated in patients with prostatic carcinoma. Further work is required to determine the role of kisspeptin in the prostate.

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GPR54 and Kisspeptins

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Results and Problems in Cell Differentiation

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The G-protein coupled receptor GPR54 has an essential role in the initiation and maintenance of mammalian fertility. Humans and mice with mutations in GPR54 have hypogonadotropic hypogonadism characterized by absence of sexual maturation and low levels of gonadotropic hormones (LH and FSH). The ligand for GPR54 is encoded by the KISS1 gene, which produces a 54-amino-acid peptide (metastin or kisspeptin-54) that can be cleaved into shorter peptides (kisspeptins 14, 13 and 10) with similar potencies. Kisspeptin administration stimulates gonadotropin release in several species by inducing GnRH secretion from hypothalamic GnRH neurons expressing GPR54. Kisspeptins are produced by neurons located in the AVPV and ARC regions of the hypothalamus. Expression of Kiss1 in these neurons is differentially regulated by sex steroids providing a mechanism by which testosterone or estrogen can regulate GnRH release. The AVPV region is sexually dimorphic with highest expression of kisspeptin in females. Positive feedback by estrogen on expression of Kiss1 in the AVPV region may be responsible for the pre-ovulatory LH surge during the estrus cycle. Central administration of kisspeptin to immature female rats can induce precocious activation of the gonadotropic axis, causing advanced vaginal opening, elevated uterus weight, increased serum levels of LH and estrogen and induce ovulation. Kisspeptins/GPR54 have also been implicated in regulating the estrus cycle of seasonal breeders and in the control of lactational amenorrhea. Expression of Gpr54 and Kiss1 have also been reported in several peripheral tissues including the pituitary, ovary, testes and the placenta raising the possibility that these genes may have additional functions in these tissues. Regulation of kisspeptin expression by peripheral factors such as leptin may be involved in coordinating metabolic status with the reproductive axis.

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Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment

Abstract: . Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment.

Cited by 68 publications

References 42 publications

Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats

Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats

Kisspeptin is released from human prostate cancer cell lines but plasma kisspeptin is not elevated in patients with prostate cancer

GPR54 and Kisspeptins

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