kiss1-protein--human has been researched along with Neoplasms* in 21 studies
16 review(s) available for kiss1-protein--human and Neoplasms
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KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers?
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells. Topics: Genes, Tumor Suppressor; Humans; Kisspeptins; Neoplasm Metastasis; Neoplasms | 2023 |
KISS1 in metastatic cancer research and treatment: potential and paradoxes.
The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinical development in the cancer therapeutic and biomarker space. Research has focused on amino acid residues 68-121 (kisspeptin 54), binding to the KISS1 receptor and cellular responses. Evidence and counterevidence regarding this canonical pathway require closer look at the covariates so that the incredible potential of KISS1 can be realized. Topics: Animals; Epigenesis, Genetic; Humans; Kisspeptins; Neoplasm Metastasis; Neoplasms; Polymorphism, Single Nucleotide; Receptors, Kisspeptin-1 | 2020 |
The role of kisspeptin system in cancer biology.
Kisspeptins are a family of neuropeptides that are known to be critical in puberty initiation and ovulation. Apart from that kisspeptin derived peptides (KPs) are also known for their antimetastatic activities in several malignancies. Herein we report recent evidence of the role of kisspeptins in cancer biology and we examine the prospective of targeting the kisspeptin pathways leading to a better prognosis in patients with malignant diseases. Topics: Animals; Female; Humans; Kisspeptins; Male; Neoplasms; Receptors, Kisspeptin-1; Signal Transduction | 2019 |
KiSS1 in regulation of metastasis and response to antitumor drugs.
Metastatic dissemination of tumor cells represents a major obstacle towards cancer cure. Tumor cells with metastatic capacity are often resistant to chemotherapy. Experimental efforts revealed that the metastatic cascade is a complex process that involves multiple positive and negative regulators. In this respect, several metastasis suppressor genes have been described. Here, we review the role of the metastasis suppressor KiSS1 in regulation of metastasis and in response to antitumor agents. Physiologically, KiSS1 plays a key role in the activation of the hypothalamic-pituitary-gonadal axis regulating puberty and reproductive functions. KiSS1-derived peptides i.e., kisspeptins, signal through the G-protein coupled receptor GPR54. In cancer, KiSS1 signaling suppresses metastases and maintains dormancy of disseminated malignant cells, by interfering with cell migratory and invasive abilities. Besides, KiSS1 modulates glucose and lipid metabolism, by reprogramming energy production towards oxidative phosphorylation and β-oxidation. Loss or reduced expression of KiSS1, in part through promoter hypermethylation, is related to the development of metastases in various cancer types, with some conflicting reports. The poorly understood role of KiSS1 in response to chemotherapeutic agents appears to be linked to stimulation of the intrinsic apoptotic pathway and inhibition of cell defense factors (e.g., glutathione S-transferase-π) as well as autophagy modulation. Deciphering the molecular basis underlying regulation of the metastatic potential is crucial for the establishment of novel treatment strategies. Topics: Animals; Antineoplastic Agents; Humans; Kisspeptins; Neoplasm Metastasis; Neoplasms; Signal Transduction | 2019 |
Regulation of Kisspeptin mediated signaling by non-coding RNAs in different cancers: the beginning of a new era.
Kisspeptin-driven intracellular signaling has captured enormous attention because of its central role in cancer onset and progression. Wealth of information has helped us to develop a better understanding of the critical roles of Kisspeptin-mediated signaling in different cancers. However, astonishingly, we have not yet drilled down deep into the mysterious aspects associated with non-coding RNA mediated regulation of Kisspeptin-driven signaling. Therefore, in this mini-review, we will comprehensively analyze available evidence related to miRNAs and long non-coding RNAs (LncRNAs) and their ability to modulate Kisspeptin-mediated signaling. There are visible knowledge gaps about interplay between non-coding RNAs and Kisspeptin-mediated signaling. It will be appropriate to say that we have just started to scratch the surface of an entirely new regulatory layer of Kisspeptin-mediated transduction cascade. Mechanistically, it has been revealed that inhibition of Kisspeptin mediated signaling activated and stimulated the entry of NFκB into the nucleus to stimulate expression of proteins which can sequentially inactivate tumor suppressor miRNAs. miRNAs have also an instrumental role in regulation of proteins which post-translationally modify and inhibit KISS1 expression. It is becoming progressively more understandable that LncRNAs act as miRNA sponges and protect oncogenic mRNAs. However, these facets are also incompletely investigated. Identification of LncRNAs which interfere with Kisspeptin-mediated pathway either through acting as miRNA sponges or working with methylation-associated machinery will be helpful in sharpening the resolution of the pixels of the regulatory network which shapes Kisspeptin-mediated signaling. Topics: Animals; Humans; Kisspeptins; MicroRNAs; Models, Biological; Neoplasms; RNA, Long Noncoding; Signal Transduction | 2019 |
Minireview: The Epigenetic Modulation of
Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preserving health status and to developing targeted interventions. In this minireview, we summarize the epigenetic modulation of the Topics: Animals; Epigenesis, Genetic; Humans; Kisspeptins; Neoplasms; Reproduction | 2019 |
Kisspeptin Mediated Signaling in Cancer.
Research over the years has gradually and sequentially highlighted contributory role of hypothalamic- based kisspeptin-signaling axis as a major positive modulator of the neuroendocrinological reproductive axis in mammals. However, a series of landmark studies provided convincing evidence of role of this signaling in regulation of cancer development and progression. It is becoming progressively more understandable that loss or reduction of KISS1 expression in different human cancers correlates inversely with progression of tumor, metastasizing potential and survival. In this review we have attempted to provide an overview highlight of the most recent updates addressing metastasis- suppressing role of KISS1. We also summarize interplay of microRNA and KISS1 in cancer. The miRNA regulation of different genes is a rapidly expanding area of research however, the community lacks a deep understanding of miRNA regulation of KISS1. Recently, emerging laboratory findings have shown that KISS1 is transcriptionally controlled by TCF21 that is in turn regulated by miR-21. Therefore, there is an urgent need for further study of how miRNA directly or indirectly influences KISS1 at the posttranscriptional level. There is also a lack of evidence regarding natural agents that mediate upregulation or downregulation of KISS1. Increasing the knowledge of the KISS1/KISS1R signaling axis will be helpful in achieving personalized medicine. Topics: Animals; Cell Death; Clinical Trials as Topic; Heterografts; Humans; Kisspeptins; Mice; Naturopathy; Neoplasms; Signal Transduction | 2016 |
The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism.
Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in the context of tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells' sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these findings reveal mitochondrial oxidative metabolism as a critical suppressor of metastasis and justify metabolic therapies for potential prevention/intervention of tumor metastasis. Topics: Anoikis; Cell Proliferation; Citric Acid Cycle; Glucose; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kisspeptins; Lactic Acid; Mitochondria; Neoplasm Metastasis; Neoplasms; Oxidative Phosphorylation; Oxidative Stress; Pyruvic Acid; Reactive Oxygen Species; Snail Family Transcription Factors; Transcription Factors; Tumor Suppressor Protein p53 | 2015 |
Kisspeptin signalling and its roles in humans.
Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors are expressed by neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus. Oestrogen mediates negative feedback of gonadotrophin-releasing hormone secretion via the arcuate nucleus. Conversely, it exerts positive feedback via the anteroventral periventricular nucleus. The sexual dimorphism of these nuclei accounts for the differential behaviour of the hypothalamic-pituitary-gonadal axis between genders. Kisspeptins are essential for reproductive function. Puberty is regulated by the maturation of kisspeptin neurons and by interactions between kisspeptins and leptin. Hence, kisspeptins have potential diagnostic and therapeutic applications. Kisspeptin agonists may be used to localise lesions in cases of hypothalamic-pituitary-gonadal axis dysfunction and evaluate the gonadotrophic potential of subfertile individuals. Kisspeptin antagonists may be useful as contraceptives in women, through the prevention of premature luteinisation during in vitro fertilisation, and in the treatment of sex steroid-dependent diseases and metastatic cancers. Topics: Animals; Arcuate Nucleus of Hypothalamus; Estrogens; Feedback, Physiological; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Kisspeptins; Male; Mice; Neoplasms; Neurons; Protein Binding; Rats; Reproduction; Sex Factors; Signal Transduction | 2015 |
The Kiss-1/Kiss-1R complex as a negative regulator of cell motility and cancer metastasis (Review).
Metastasis is a complex multistep process that involves the impairment of cell-cell adhesion in the neoplastic epithelium, invasion into adjacent tissues and the dissemination of cancer cells through the lymphatic and haematogenous routes. The inhibition of the metastatic process at an early stage has become a hot topic in cancer research. The Kiss-1 gene, initially described as a suppressor of metastasis in malignant melanoma, encodes the Kiss-1 protein which can be processed to other peptides, e.g., Kisspeptin-10, Kisspeptin-13, Kisspeptin-14 and Kisspeptin-54. These peptides are endogenous ligands of the Kiss‑1 receptor (Kiss-1R), a G protein-coupled receptor (GPR) also known as hOT7T175, AXOR12 or GPR54. The Kiss-1 gene has been suggested as a suppressor of metastasis in a various types of cancer, including gastric cancer, oesophageal carcinoma, pancreatic, ovarian, bladder and prostate cancer, through the regulation of cellular migration and invasion. In the current review, we summarise the current understanding of the role of Kiss‑1 and Kiss‑1R in cancer and cancer metastasis. Topics: Cell Adhesion; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Ligands; Neoplasm Metastasis; Neoplasms; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1 | 2013 |
KiSS1 and its G-protein-coupled receptor GPR54 in cancer development and metastasis.
KiSS1 and its cognate G-protein-coupled receptor, GPR54, have diverse functions. While KiSS1 and GPR54 have been intensively studied in physiology, their role in cancer is still unclear. In cancer, KiSS1 and GPR54 have been known to suppress metastasis by inhibiting cancer cell motility. However, recent studies suggest that KiSS1 and GPR54 have varied roles even in cancer development and metastasis. Here, we examine recent advances in understanding the roles of KiSS1 and GPR54 in cancer development and metastasis. Topics: Animals; Humans; Kisspeptins; Neoplasm Metastasis; Neoplasms; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Signal Transduction | 2012 |
Regulation of KiSS1 gene expression.
Kisspeptins are the protein products encoded by KiSS1 gene, an important tumor metastatic suppressor and pivotal master hormone of puberty. Although KiSS1 gene is expressed in both central and peripheral tissues, the molecular mechanisms that determine the temporal and spatial expression of KiSS1 gene are not well understood. This review provides an update on the latest studies and ideas about the expression of KiSS1 gene as a puberty gatekeeper and a metastasis suppressor, with special emphasis on the molecular mechanisms for the transcriptional regulation of KiSS1 gene expression. Topics: Cell Line, Tumor; Gene Expression Regulation; Gonads; Humans; Hypothalamo-Hypophyseal System; Kisspeptins; Neoplasms; Tissue Distribution; Transcription, Genetic; Tumor Suppressor Proteins | 2009 |
GPR54 and kisspeptins.
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. Topics: Amino Acid Sequence; Animals; Gene Expression Regulation; Humans; Hypothalamus; Kisspeptins; Ligands; Mice; Molecular Sequence Data; Mutation; Neoplasms; Neurons; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Tumor Suppressor Proteins | 2008 |
Neuroendocrine factors in the initiation of puberty: the emergent role of kisspeptin.
Puberty is the end-point of a complex series of developmental events, defined by the dynamic interaction between genetic factors and environmental cues, ultimately leading to the attainment of reproductive capacity. The neuroendocrine basis of puberty has been the subject of extensive investigation in the last decades, and identification of the trigger(s) of puberty onset has drawn considerable attention. In this context, recognition of the fundamental role of kisspeptin (encoded by the KiSS-1 gene) and its receptor GPR54 as major gatekeepers of gonadotropic function in general, and puberty onset in particular, has been a major breakthrough in contemporary Neuroendocrinology. Indeed, during the last 3 years, the so-called KiSS-1/GPR54 system has been substantiated as pivotal regulator of puberty in mammals; the lack of GPR54 signaling being coupled to sexual immaturity (impuberism) in mice and humans. In this review, we will summarize the most salient experimental data (mostly obtained in laboratory animals) demonstrating the key roles of hypothalamic KiSS-1 neurons in the activation of the reproductive axis at puberty, and its regulation by metabolic and, eventually, environmental factors. Whether the KiSS-1 system is the trigger for puberty onset and/or it operates as integrator and effector of up-stream regulatory factors warrants further investigation. Topics: Animals; Environment; Humans; Kisspeptins; Leptin; Neoplasms; Neurosecretory Systems; Puberty; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Rodentia; Sexual Maturation; Tumor Suppressor Proteins | 2007 |
Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system.
Orphan G-protein-coupled receptors that have recently been paired with their cognate ligand are an often untapped resource for novel drug development. The KISS1 receptor (previously designated GPR54) has been paired with biologically active cleavage peptides of the KiSS-1 gene product, the kisspeptins (KP). The focus of this review is the emerging pharmacology and physiology of the KP. Genetic linkage analysis in humans revealed that mutations in KISS1 (GPR54, AXOR12 or hOT7T175) result in idiopathic hypogonadotrophic hypogonadism and knockout mouse studies confirmed this finding. Identification of KISS1 (GPR54) as a molecular switch for puberty subsequently led to the discovery that KP activate the GnRH cascade. Prior to the role of KISS1 (GPR54) in puberty being described, KP had been shown to be inhibitors of tumour metastasis across a range of cancers. Subsequently the mechanism of this inhibition has been suggested to be via altered cell motility and adhesiveness. PCR detected highest expression of KP and KISS1 (GPR54) in placenta, and changes in KP levels throughout pregnancy and expression in trophoblasts suggests a role in placentation. Placentation and metastasis are invasive processes that require angiogenesis. Investigation of KISS1 (GPR54) and KP in vasculature revealed discrete localisation of KISS1 (GPR54) to blood vessels prone to atherosclerosis and a potent vasoconstrictor action. A role for KP has also been shown in whole body homeostasis. KP are multifunctional peptides and further investigation is required to fully elucidate the complex pathways regulated by these peptides and how these pathways integrate in the whole body system. Topics: Cardiovascular System; Drug Delivery Systems; Humans; Kisspeptins; Neoplasm Metastasis; Neoplasms; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Tumor Suppressor Proteins | 2007 |
Discovery of novel regulatory peptides by reverse pharmacology: spotlight on chemerin and the RF-amide peptides metastin and QRFP.
Reverse pharmacology is a screening technology that matches G protein-coupled receptors (GPCRs) with unknown cognate ligands in cell-based screening assays by detection of agonist-induced signaling pathways. One decade spent pursuing orphan GPCR screening by this technique assigned over 30 ligand/receptor pairs and revealed previously known or novel undescribed ligands, mostly of a peptidic nature. In this review, we describe the discovery, characterization of the structural composition, biological function, physiological role and therapeutic potential of three recently identified peptidic ligands. These are metastin, QRFP in a context of five RF-amide genes described in humans and the chemoattractant, chemerin. Metastin was initially characterized as a metastasis inhibitor. Investigations using ligand/receptor pairing revealed that metastin was involved in a variety of physiological processes, including endocrine function during pregnancy and gonad development. The novel RF-amide QRFP is implicated in food intake and aldosterone release from the adrenal cortex in the rat. Chemerin, first described as TIG2, is upregulated in tazarotene-treated psoriatic skin. By GPCR screening, bioactive chemerin was isolated from ovarial carcinoma fluid as well as hemofiltrate. Characterization as a chemoattractant for immature dendritic cells and analysis of the expression profile of metastin and its receptor suggested a physiological role of chemerin as a mediator of the immune response, inflammatory processes and bone development. Topics: Amino Acid Sequence; Animals; Chemokines; Drug Evaluation, Preclinical; Female; Humans; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Kisspeptins; Ligands; Models, Biological; Molecular Sequence Data; Neoplasms; Oligopeptides; Pharmacology; Pregnancy; Proteins; Rats; Receptors, G-Protein-Coupled; Signal Transduction; Trophoblasts; Tumor Suppressor Proteins | 2005 |
5 other study(ies) available for kiss1-protein--human and Neoplasms
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Editorial: The versatile kisspeptin: advances in cancer, metabolism, and reproduction.
Topics: Humans; Kisspeptins; Luteinizing Hormone; Neoplasms; Reproduction | 2023 |
Functional analysis of the emerging roles for the KISS1/KISS1R signaling pathway in cancer metastasis.
Cancer metastasis, a process that primary tumor cells disseminate to secondary organs, is the most lethal and least effectively treated characteristic of human cancers. Kisspeptins are proteins encoded by the KISS1 gene that was originally described as a melanoma metastasis suppressor gene. Then, Kisspeptins were discovered as the natural ligands of the G-protein-coupled receptor 54 (GPR54) that is also called KISS1R. The KISS1/KISS1R signaling is essential to control GnRH secretion during puberty and to establish mammalian reproductive function through the hypothalamic-pituitary-gonadal (HPG) axis. Although KISS1 primarily plays a suppressive role in the metastasis progression in several cancer types, emerging evidence indicates that the physiological effect of KISS1/KISS1R in cancer metastasis is tissue context-dependent and still controversial. Here, we will discuss the epigenetic mechanism involved in the regulation of KISS1 gene expression, the context-dependent role of KISS1/KISS1R, prometastasis/anti-metastasis signaling pathways of KISS1/KISS1R, and the perspective anticancer therapeutics via targeting KISS1/KISS1R. Topics: Animals; Genes, Tumor Suppressor; Humans; Kisspeptins; Mammals; Neoplasms; Proteins; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Signal Transduction | 2022 |
Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2.
Kisspeptin is a protein encoded by the KISS1 gene, which has been reported to suppress the metastatic capabilities of various types of cancer cells, through the activation of its G‑protein coupled receptor GPR54. However, the molecular mechanisms underlying the involvement of kisspeptin‑mediated signaling in the inhibition of cancer cell migration and invasion have yet to be elucidated. The present in vitro cell proliferation, migration and invasion assays and in vivo experimental metastasis studies demonstrated that kisspeptin‑induced eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) activation suppressed the metastatic capabilities of several types of cancer cells. Kisspeptin was revealed to inhibit the migratory and invasive abilities of highly metastatic breast SK‑BR‑3, prostatic PC‑3 and colorectal adenocarcinoma LoVo human cancer cell lines, whereas its inhibitory effects were abolished following the silencing of EIF2AK2 expression using RNA interference. Similarly, kisspeptin failed to inhibit the migration and invasion of mouse embryonic fibroblasts following the deletion of the EIF2AK2 gene. Furthermore, kisspeptin was demonstrated to activate Ras homolog gene family member A (RhoA)‑dependent signaling, and to phosphorylate EIF2AK2 via RhoA‑mediated pathways in various cancer cells. In addition, results obtained from nude mice bearing LoVo‑derived xenograft tumors revealed that kisspeptin inhibited tumor growth through an EIF2AK2‑dependent mechanism, and an in vivo metastasis assay identified kisspeptin‑activated EIF2AK2 signaling as critical for the suppression of distant metastasis. The present study concluded that kisspeptin represses cancer metastasis via EIF2AK2 signaling, thus clarifying the role of kisspeptin signaling in complicated cancer metastasis signaling network. Therefore, kisspeptin treatment may be a choice for blocking metastases. Topics: Animals; Cell Line; Cell Movement; Cell Proliferation; eIF-2 Kinase; Humans; Kisspeptins; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasms; Phosphorylation; rhoA GTP-Binding Protein; RNA Interference; RNA, Small Interfering; Transplantation, Heterologous | 2017 |
Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis.
Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30% to 50% more mitochondrial mass than ΔSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master coactivator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e., fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using short hairpin RNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis. Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Extracellular Space; Female; Gene Expression; Glucose; Glycolysis; Humans; Hydrogen-Ion Concentration; Kisspeptins; Lactic Acid; Mice; Mitochondria; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors | 2014 |
Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity.
Metastin has been identified as a metastasis suppressor gene product that mediates its function through a G protein coupled receptor, GPR54. To refine insight into the critical pharmacophore for the activation of GPR54, we have conducted alanine and d-amino acid scanning on a biologically active metastin fragment (45-54). Based on these data and structures of peptides previously reported to activate GPR54, a series of shortened metastin (45-54) derivatives were synthesized and tested for the ability to induce GPR54 signaling. These biological experiments were performed in yeast containing human GPR54 that was coupled to the pheromone response pathway and a pheromone responsive lacZ reporter gene. Compounds 32, 33, and 39, which possess an N-terminal basic group and a C-terminal RW-amide motif, were strong agonists, similar to the level of metastin. This may provide an approach to reverse the pro-metastatic effect of metastin deletion in multiple malignant tumors. Topics: Amino Acid Motifs; Amino Acid Sequence; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Design; Fungal Proteins; Genes, Reporter; Humans; Kisspeptins; Lac Operon; Models, Chemical; Molecular Sequence Data; Neoplasms; Peptides; Pheromones; Protein Binding; Protein Structure, Tertiary; Proteins; Receptors, G-Protein-Coupled; Receptors, Galanin; Receptors, Kisspeptin-1; Tumor Suppressor Proteins | 2006 |