Silencing of the GnRH Type 1 Receptor Blocks the Antiproliferative Effect of the GnRH Agonist, Leuprolide, on the Androgen-Independent Prostate Cancer Cell Line DU145

Ko, Young Hwii; Ha, Yushin; Kim, J W; Kang, Seongman; Jang, Hyon Seok; Kang, Seok Ho; Park, H S; Cheon, Jun

doi:10.1177/147323001103900304

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…Multiple in vitro studies have shown that LHRH agonists exert an antiproliferative effect in a dose‐dependent manner on PCa cells . For example, one investigation showed that by blocking LHRH‐R expression with silencing RNA, the antiproliferative effect of leuprorelin was inhibited, confirming that effects on proliferation are mediated via the LHRH‐R pathway .…”

Section: Clinical Implications Of Lhrh‐r Function In Models Of Pcamentioning

confidence: 99%

Luteinizing hormone‐releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors?

2013

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Luteinizing hormone-releasing hormone (LHRH) agonists and antagonists are commonly used androgen deprivation therapies prescribed for patients with advanced prostate cancer (PCa). Both types of agent target the receptor for LHRH but differ in their mode of action: agonists, via pituitary LRHR receptors (LHRH-Rs), cause an initial surge in luteinizing hormone (LH), follicle-stimulating hormone (FSH) and, subsequently, testosterone. Continued overstimulation of LHRH-R down-regulates the production of LH and leads to castrate levels of testosterone. LHRH antagonists, however, block LHRH-R signalling causing a rapid and sustained inhibition of testosterone, LH and FSH. The discovery and validation of the presence of functional LHRH-R in the prostate has led to much work investigating the role of LHRH signalling in the normal prostate as well as in the treatment of PCa with LHRH agonists and antagonists. In this review we discuss the expression and function of LHRH-R, as well as LH/human chorionic gonadotropin receptors and FSH receptors and relate this to the differential clinical responses to agonists and antagonists used in the hormonal manipulation of PCa.

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Section: Clinical Implications Of Lhrh‐r Function In Models Of Pcamentioning

confidence: 99%

Luteinizing hormone‐releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors?

2013

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Quantitative proteomic analysis of GnRH agonist treated GBM cell line LN229 revealed regulatory proteins inhibiting cancer cell proliferation

et al. 2022

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Background Gonadotropin-releasing hormone (GnRH) receptor, a rhodopsin-like G-protein coupled receptor (GPCR) family member involved in GnRH signaling, is reported to be expressed in several tumors including glioblastoma multiforme (GBM), one of the most malignant and aggressive forms of primary brain tumors. However, the molecular targets associated with GnRH receptor are not well studied in GBM or in other cancers. The present study aims at investigating the effect of GnRH agonist (Gosarelin acetate) on cell proliferation and associated signaling pathways in GBM cell line, LN229. Methods LN229 cells were treated with different concentrations of GnRH agonist (10−10 M to 10−5 M) and the effect on cell proliferation was analyzed by cell count method. Further, total protein was extracted from control and GnRH agonist treated cells (with maximum reduction in cell proliferation) followed by trypsin digestion, labeling with iTRAQ reagents and LC-MS/MS analysis to identify differentially expressed proteins. Bioinformatic analysis was performed for annotation of proteins for the associated molecular function, altered pathways and network analysis using STRING database. Results The treatment with different concentrations of GnRH agonist showed a reduction in cell proliferation with a maximum reduction of 48.2% observed at 10−6 M. Quantitative proteomic analysis after GnRH agonist treatment (10−6 M) led to the identification of a total of 29 differentially expressed proteins with 1.3-fold change (23 upregulated, such as, kininogen-1 (KNG1), alpha-2-HS-glycoprotein (AHSG), alpha-fetoprotein (AFP), and 6 downregulated, such as integrator complex subunit 11 (CPSF3L), protein FRG1 (FRG1). Some of them are known [KNG1, AHSG, AFP] while others such as inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2), ITIH4, and LIM domain-containing protein 1 (LIMD1) are novel to GnRH signaling pathway. Protein-protein interaction analysis showed a direct interaction of KNG1, a hub molecule, with GnRH, GnRH receptor, EGFR and other interactors including ITIH2, ITIH4 and AHSG. Overexpression of KNG1 after GnRH agonist treatment was validated using Western blot analysis, while a significant inhibition of EGFR was observed after GnRH agonist treatment. Conclusions The study suggests a possible link of GnRH signaling with EGFR signaling pathways likely via KNG1. KNG1 inhibitors may be investigated independently or in combination with GnRH agonist for therapeutic applications.

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GnRH-(1–5) Transactivates EGFR in Ishikawa Human Endometrial Cells via an Orphan G Protein-Coupled Receptor

Cho-Clark

Larco

Semsarzadeh³

et al. 2014

Molecular Endocrinology

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The decapeptide GnRH is known for its central role in the regulation of the hypothalamo-pituitary-gonadal axis. In addition, it is also known to have local effects within peripheral tissues. The zinc metalloendopeptidase, EC 3.4.24.15 (EP24.15), can cleave GnRH at the Tyr(5)-Gly(6) bond to form the pentapeptide, GnRH-(1-5). The central and peripheral effect of GnRH-(1-5) is different from its parent peptide, GnRH. In the current study, we examined the effect of GnRH-(1-5) on epidermal growth factor receptor (EGFR) phosphorylation and cellular migration. Using the Ishikawa cell line as a model of endometrial cancer, we demonstrate that GnRH-(1-5) stimulates epidermal growth factor release, increases the phosphorylation of EGFR (P < .05) at three tyrosine sites (992, 1045, 1068), and promotes cellular migration. In addition, we also demonstrate that these actions of GnRH-(1-5) are mediated by the orphan G protein-coupled receptor 101 (GPR101). Down-regulation of GPR101 expression blocked the GnRH-(1-5)-mediated release of epidermal growth factor and the subsequent phosphorylation of EGFR and cellular migration. These results suggest that GPR101 is a critical requirement for GnRH-(1-5) transactivation of EGFR in Ishikawa cells.

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Silencing of the GnRH Type 1 Receptor Blocks the Antiproliferative Effect of the GnRH Agonist, Leuprolide, on the Androgen-Independent Prostate Cancer Cell Line DU145

Cited by 4 publications

References 30 publications

Luteinizing hormone‐releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors?

Luteinizing hormone‐releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors?

Quantitative proteomic analysis of GnRH agonist treated GBM cell line LN229 revealed regulatory proteins inhibiting cancer cell proliferation

GnRH-(1–5) Transactivates EGFR in Ishikawa Human Endometrial Cells via an Orphan G Protein-Coupled Receptor

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