Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to Agonist<i>In vitro</i>and<i>In vivo</i>

Morgan, Kevin; Stewart, Alan J.; Miller, Nicola; Mullen, Peter; Muir, Morwenna; Dodds, Michael; Medda, Federico; Harrison, David J.; Langdon, Simon P.; Millar, Robert P.

doi:10.1158/0008-5472.can-08-0197

Cited by 47 publications

(62 citation statements)

References 52 publications

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“…The antiproliferative effects of GnRH-II in endometrial cancer cells may be due to increased apoptosis. Recently, Morgan and colleagues (33) reported that GnRH agonists mediated the inhibition of cell growth by the induction of apoptosis in different cells. This study also showed that GnRH receptors and intracellular signaling play an important role in the apoptotic process, contributing to the cell type-specific effects of GnRH on growth.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α

Cheng

Wang

et al. 2009

Cancer Research

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Gonadotropin-releasing hormone type II (GnRH-II) has an antiproliferative effect on human endometrial cancer cells. Apoptosis in cancer cells may play a critical role in regulating cell proliferation. However, more studies are necessary to elucidate the underlying molecular mechanisms and develop potential applications of GnRH-II. Therefore, we explored the mechanisms of GnRH-II-induced apoptosis and the effects of GnRH-II on GADD45A activation in human endometrial cancer cell lines. GnRH-II decreased cell viability in a dose-and timedependent manner. Apoptosis was induced with increased terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling apoptotic cells after GnRH-II treatment.

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Section: Discussionmentioning

confidence: 99%

Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α

Cheng

Wang

et al. 2009

Cancer Research

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“…The second and third intracellular loops are important for receptor-G protein interaction and signaling functions in GPCRs. Differences in the levels of GnRH receptor affect the GnRH-stimulated production of inositol phosphate within cells and contribute to the cell type-specific effects of GnRH (Morgan et al 2008). A specific alanine residue is involved in certain GPCRs, the equivalent of which is Ala-261 in the GnRH receptor.…”

Section: Ligand Receptor-mediated Intracellular Signal Transduction Imentioning

confidence: 99%

“…The possibility is that differences in the levels of GnRH receptor expression exist during cell passage in vitro or as a result of varied culture conditions. Consequently, differences in levels of GnRH receptor and signaling pathway individually contribute to the induction of apoptosis and play an important role in the regulation of GnRH on cell typespecific growth (Morgan et al 2008).…”

Section: Gnrh and Apoptosismentioning

confidence: 99%

GnRH signaling in intrauterine tissues

Wu¹,

Wang²,

Huang³

et al. 2009

Reproduction

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Type I GnRH (GnRH-I, GNRH1) and type II GnRH (GnRH-II, GNRH2), each encoded by separate genes, have been identified in humans. The tissue distribution and functional regulation of GnRH-I and GnRH-II clearly differ despite their comparable cDNA and genomic structures. These hormones exert their effects by binding to cell surface transmembrane G protein coupled receptors and stimulating the Gq/11 subfamily of G proteins. The hypothalamus and pituitary are the main origin and target sites of GnRH, but numerous studies have demonstrated that extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in different reproductive tissues such as the ovary, endometrium, placenta, and endometrial cancer cells. In addition to endocrine regulation, GnRH is also known to act in an autocrine and paracrine manner to suppress cell proliferation and activate apoptosis in the endometrium and endometrial cancer cells through several mechanisms. Both GnRH-I and GnRH-II exhibit regulatory roles in tissue remodelling during embryo implantation and placentation, which suggests that these hormones may have important roles in embryo implantation and early pregnancy. The presence of varied GnRH and GnRH receptor systems demonstrate their different roles in distinct tissues using dissimilar mechanisms. These may result in the generation of new GnRH analogues used for several hormone-related diseases.

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“…A direct relationship has been found between this effect of GnRH agonists and the level of GnRH receptor expression in the particular cell line. (Morgan et al, 2008) Modifications that retard the dissociation rate of the GnRH analog from its receptor have been shown to increase its biopotency and bioavailability in vivo, which are highly dependent on the peptide's stability and permeability across biological membranes. In spite of extensive research in the field of hormonal therapy and development of various GnRH agonists over the past three decades, GnRH peptide analogs still suffer from poor pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

Varamini

Mansfeld

Giddam

et al. 2017

International Journal of Pharmaceutics

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Graphical abstractGonadotropin-releasing hormone (GnRH) is an endogenous peptide with a short biological half-life. Although GnRH analogs (eg. triptorelin) are developed with enhanced stability compared to the native peptide, they still suffer from poor biological stability and pharmacokinetic properties. Furthermore, they are only effective in the treatment of hormone-dependent reproductive cancers. In this study we applied lipidation and glycosylation along with D-amino acid substitution at position 6 (D-Trp 6 ) to improve the stability, permeability, and consequently the potency of the GnRH peptide and triptorelin. We showed that the conjugation of GnRH with a lipid moiety and carbohydrates made all modified constructs (1-8) more stable than the parent peptide against enzymatic degradation (5.5 to 6.5 times). Two of the lactose-modified glycolipopeptides, 3 and 6, showed 27 and 16 times higher membrane permeability than the parent GnRH, respectively. All analogs with D-Trp 6 -substitution (4-6) exerted GnRH receptor-mediated antiproliferative activity in prostate and ovarian GnRH-receptor positive cell lines. They were more potent than triptorelin in the hormone-independent prostate cancer cell line: DU145. Compound 6 (lactose-modified) was the most potent analog for stimulating the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) gonadotropins from rat pituitary cells in vitro. The same glycolipopeptide exhibited a higher efficacy and duration of action in stimulating the release of LH than triptorelin in a preclinical mouse model. The superior activity 2 of lipid-and carbohydrate-substituted triptorelin analog 6 made it a promising candidate for the development of new GnRH agonists to treat both hormone-dependent and hormone-refractory prostate cancer..LIST OF ABBREVIATIONS

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Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to AgonistIn vitroandIn vivo

Cited by 47 publications

References 52 publications

Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α

Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α

GnRH signaling in intrauterine tissues

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

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