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Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility.

ABSTRACT: Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cell lines U-118, U-87, CCF-STTG1, and SW1088 express 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes. The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility. In addition, ghrelin led to actin polymerization and membrane ruffling on cells, with the specific co-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and imparting the tumor cells with a motile phenotype. Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished motility, matrix metalloproteinase activity, and Rac expression, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility. The relevance of ghrelin and GHS-R expression was verified in clinically relevant tissues from 20 patients with oligodendrogliomas and grade II-IV astrocytomas. Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones. Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin.

SUBMITTER: Dixit VD

PROVIDER: S-EPMC2271047 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility.

Dixit Vishwa Deep VD Weeraratna Ashani T AT Yang Hyunwon H Bertak Dorothy D Cooper-Jenkins Anthony A Riggins Gregory J GJ Eberhart Charles G CG Taub Dennis D DD

The Journal of biological chemistry 20060309 24

Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cel ...[more]

PMID: 16527811

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Project description:The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the ghrelin/GHS-R system.

Project description:The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.

Project description:BackgroundCluster of differentiation 4 (CD4+) T cells plays a prominent role in eliminating cancer cells. The balance between T helper (Th)17 and regulatory T (Treg) cells is crucial for optimal immune response and protection against cancer. Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled protein receptor superfamily, plays a critical role in immune cell function. The aim of our study is to investigate the role of GHSR1a in CD4+ T cell differentiation and lung cancer progression.MethodsA subcutaneous lung cancer model was used to examine the role of GHSR1a in controlling tumor growth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into Ghsr1a -/- mice and wild-type (WT) mice. The ratio of Th17 and Treg in the draining lymph node of Ghsr1a -/- mice and WT tumor-bearing mice was detected by fluorescence-activated cell sorting (FACS). The effect of GHSR1a deficiency on Th17 and Treg cell differentiation was examined using an in vitro differentiation assay. The phosphorylation of mammalian target of rapamycin (mTOR), signal transducer, and activator of transcription (STAT)3 and STAT5 signaling was detected with Western blot.ResultsWe found that the ablation of GHSR1a resulted in impaired anti-tumor immunity to control lung cancer growth in vivo. We also demonstrated that the deficiency of GHSR1a promoted a shift in the Th17/Treg balance toward enhanced Treg differentiation and inhibited Th17 differentiation both in vivo and in vitro, which suggests that GHSR1a regulates T cell lineage choices between Th17 and Treg cell commitment in the tumor microenvironment. Mechanistically, the deficiency of GHSR1a resulted in reduced phosphorylation in mTOR and STAT3, and increased phosphorylation in STAT5.ConclusionsOur findings showed the important role of GHSR1a in CD4+ T cell differentiation in the context of the lung cancer microenvironment. This research provides a novel molecular target and insights into interventions for the prevention and treatment of lung cancer.

Dataset Information

Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility.

Publications

Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility.

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