Kisspeptin Effect on Endothelial Monocyte Activating Polypeptide II (EMAP-II)-Associated Lymphocyte Cell Death and Metastases in Colorectal Cancer Patients

Stathaki, Martha; Armakolas, Athanasios; Dimakakos, Andreas; Kaklamanis, Loukas; Vlachos, Ioannis S.; Konstantoulakis, Manoussos M.; Zografos, George; Koutsilieris, Michael

doi:10.2119/molmed.2013.00151

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…Summarizing the results obtained, it can be argued that kisspeptin-54 is directly involved in the regulation of PBMC apoptosis, which is obviously an important mechanism for controlling the activation of these cells during pregnancy. Stathaki, M. and co-authors also showed that kisspeptin-54 induces apoptosis of lymphocytes in vitro [14]. In addition, we have shown that kisspeptin-54 promotes the formation of peripheral tolerance by stimulating IDO activity.…”

Section: Modulation Of Ido Activity By Kisspeptin-54supporting

confidence: 62%

Regulation of kisspeptin-54 activity of indolamine-2,3-dioxygenase and apoptosis of peripheral blood lymphocytes

Gorbunova

Shirshev

2023

Med. immunol.

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Pregnancy is a phenomenon of natural semi-allogeneic transplantation, since the fetus is half alien due to the expression of paternal antigens. It was found that the hypothalamic hormone kisspeptin during pregnancy is produced by the syncytiotrophoblast of the placenta and participates in the formation of a new specific hormonal background. Several forms of the hormone circulate in the blood of pregnant women: kisspeptin-10, kisspeptin-14 and kisspeptin-54 (according to the number of amino acid residues in the hormone molecule), but the main active form is kisspeptin-54. The main mechanism for the formation of immune tolerance during pregnancy is the induction of the expression of the enzyme indolamine-2,3- dioxygenase (IDO) by antigen-presenting cells of peripheral blood, resulting in the catalysis of tryptophan (Trp) to kynurenins (KYN) blocking the activation and causing apoptosis of cytotoxic CD8+T lymphocytes in the zone of contact of maternal immune cells with placental-fetal complex antigens. In addition, during pregnancy, an important role is assigned to the process of apoptosis, since activated cells can be potentially dangerous for the developing fetus. Immunocompetent blood cells express a specific membrane receptor of kisspeptin (KISS-1R). Since kisspeptin-54 enters the systemic circulation only during pregnancy, the hormone has an effect on immune cells only during this period.The aim of this work was to evaluate the effect of kisspeptin-54 in concentrations comparable to its levelduring physiological pregnancy on IDO activity and apoptosis of peripheral blood lymphocytes.Peripheral blood mononuclear cells (PBMC) obtained from 10 healthy non-pregnant women of reproductive age (from 23 to 32 years) were used as the object of the study. Lymphocyte apoptosis was assessed in PBMC suspension by staining with annexin-V and propidium iodide. The determination of the number of cells in the early and late stages of apoptosis was carried out in the isolated gate of lymphocytes. IDO activity in PBMC was determined spectrophotometrically by changes in the concentration of KYN, the first stable metabolite of the Trp decay pathway.It was found that kisspeptin-54 at a concentration of 4.6 pM corresponding to the second trimester of pregnancy significantly enhances the activity of IDO, increases the number of cells in the early and late stages of apoptosis. Thus, kisspeptin-54 is an important mechanism for controlling these processes during pregnancy, aimed at protecting the semi-allogeneic fetus from adverse immune reactions of the mother and the favorable development of pregnancy.

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Section: Modulation Of Ido Activity By Kisspeptin-54supporting

confidence: 62%

Regulation of kisspeptin-54 activity of indolamine-2,3-dioxygenase and apoptosis of peripheral blood lymphocytes

Gorbunova

Shirshev

2023

Med. immunol.

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“…The KP/GPR54 signaling pathway plays an important role in initiating the secretion of gonadotropin-releasing hormone (GnRH) at puberty, and is involved in the regulation of the GnRH/GnRH receptor (GnRHR) signaling pathway (6). Previous research has provided substantial evidence supporting the role of the KISS-1/GPR54 signaling pathway in the regulation of the reproductive axis, including the timing of puberty, the sexual differentiation of the brain, the regulation of GnRH at puberty, as well as in diabetes, adiposity, atherogenesis (7), gastrointestinal motility (8), learning and memory (9), and suppression of metastasis across a range of cancer types (10,11).…”

Section: Introductionmentioning

confidence: 99%

Kisspeptin‑13 inhibits bleomycin‑induced pulmonary fibrosis through GPR54 in mice

Lei

Xue

et al. 2019

Mol Med Report

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Kisspeptin (KP) is an amidated neurohormone that is encoded by the KiSS-1 metastasis suppressor (KISS1) gene and serves as the endogenous ligand for G protein-coupled receptor 54 (GPR54). KP is involved in the regulation of several biological functions, such as reproduction, cancer and atherogenesis. Recent data suggested that KP may induce atherosclerotic plaque progression and instability, which may be reversed by the GPR54 antagonist KP-234. Despite the KISS1 gene being previously reported as a downstream target of the classic transforming growth factor (TGF)/Smad2 signaling pathway, its role in fibrosis remains elusive. The purpose of the present study was to evaluate the role of KP-13 (a product of the KISS1 gene) in a bleomycin (BLM)-induced idiopathic pulmonary fibrosis model. Lung tissue samples were evaluated by quantitative PCR analysis, western blotting and ELISA. Daily intraperitoneal administration of KP-13 significantly ameliorated body weight loss, histopathological lung abnormalities and pulmonary collagen deposition induced by BLM. Furthermore, KP-13 downregulated the expression levels of tumor necrosis factor-α, TGF-β, collagen type I α1, actin α2 and matrix metalloproteinase 2 in BLM-treated lungs compared with BLM group. Notably, the production of α-smooth muscle actin in lung tissues, as well as the pulmonary levels of TGF-β1 and phosphorylated-Smad2/3, was reduced following treatment with KP-13. The anti-fibrotic effects of KP-13 were reversed by KP-234 (an antagonist of GPR54), but not by Cetrorelix (an antagonist of the gonadotropin-releasing hormone receptor). Furthermore, apoptosis-related proteins, such as Bax and caspase-3, were decreased, whereas Bcl-2 was markedly increased as determined by western blotting. Collectively, these data suggested that the KP/GPR54 signaling pathway may be a promising target for the treatment of idiopathic pulmonary fibrosis.

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“…EMAP II could suppress the growth of primary and metastatic tumors and induce apoptosis in growing endothelial cells ( Schwarz et al, 2010a ). Elevated EMAP II expression was associated with lymphocyte apoptosis and lack of metastases in colon cancer patients ( Stathaki et al, 2014 ). The in vivo study reported that EMAP II attenuated the primary tumor growth of rat C6 glioma cells ( Schwarz and Schwarz, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Autophagy Induction by Endothelial-Monocyte Activating Polypeptide II Contributes to the Inhibition of Malignant Biological Behaviors by the Combination of EMAP II with Rapamycin in Human Glioblastoma

Meng

et al. 2015

Front. Mol. Neurosci.

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This study aims to investigate the effect of endothelial-monocyte activating polypeptide II (EMAP II) on human glioblastoma (GBM) cells and glioblastoma stem cells (GSCs) as well as its possible mechanisms. In this study, EMAP II inhibited the cell viability and decreased the mitochondrial membrane potential in human GBM cells and GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) blocked these effects. Autophagic vacuoles were formed in these cells after EMAP II treatment and this phenomenon was blocked by 3-MA. In addition, the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and the down-regulation of autophagic degraded substrate p62/SQSTM1 caused by EMAP II were observed. Cells treated with EMAP-II inhibited the PI3K/Akt/mTOR signal pathway, and PI3K/Akt agonist insulin-like growth factor-1 (IGF-1) blocked the effect of EMAP II on the expression of LC3-II and p62/SQSTM1. Cells exposed to EMAP-II experienced mitophagy and ER stress. Furthermore, the inhibition of cell proliferation, migration and invasion of GBM cells and GSCs were more remarkable by the combination of EMAP II and rapamycin than either agent alone in vitro and in vivo. The current study demonstrated that the cytotoxicity of EMAP II in human GBM cells and GSCs was induced by autophagy, accompanied by the inhibition of PI3K/Akt/mTOR signal pathway, mitophagy and ER stress. The combination of EMAP II with rapamycin demonstrated the inhibitory effect on the malignant biological behaviors of human GBM cells and GSCs in vitro and in vivo.

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Kisspeptin Effect on Endothelial Monocyte Activating Polypeptide II (EMAP-II)-Associated Lymphocyte Cell Death and Metastases in Colorectal Cancer Patients

Cited by 13 publications

References 29 publications

Regulation of kisspeptin-54 activity of indolamine-2,3-dioxygenase and apoptosis of peripheral blood lymphocytes

Regulation of kisspeptin-54 activity of indolamine-2,3-dioxygenase and apoptosis of peripheral blood lymphocytes

Kisspeptin‑13 inhibits bleomycin‑induced pulmonary fibrosis through GPR54 in mice

Autophagy Induction by Endothelial-Monocyte Activating Polypeptide II Contributes to the Inhibition of Malignant Biological Behaviors by the Combination of EMAP II with Rapamycin in Human Glioblastoma

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