Mechanism of gonadotropin-releasing hormone (GnRH)-I and -II-induced cell growth inhibition in ovarian cancer cells: role of the GnRH-I receptor and protein kinase C pathway

Kim, Ki-Yon; Choi, Kyung‐Chul; Auersperg, Nelly; Leung, Peter C.K.

doi:10.1677/erc.1.01033

Cited by 58 publications

(49 citation statements)

References 41 publications

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“…In addition, cotreatment of cells with the GnRH antagonist antide, which is known to inhibit the functional activity of GnRH receptor (Li et al, 1994) and its downstream signaling (Kim et al, 2006), also prevented the upregulation of P-cadherin (Figure 1d), confirming a direct involvement of GnRH receptor in regulating P-cadherin expression. The increase in P-cadherin was not the result of changes in mRNA stability, as GnRHa did not affect the turnover rate of the P-cadherin mRNA (Figure 2a).…”

Section: Resultsmentioning

confidence: 66%

“…inhibiting the GnRH receptor in the absence of GnRHa in these cells (Kang et al, 2000;Cheung et al, 2006;Kim et al, 2006), an autocrine system might exist in vivo. It is known that the GnRH precursor must be cleaved to become active (Cheng and Leung, 2005), and the lack of response with GnRH receptor inhibition in Figure 7 Cytoplasmic localization of p120 ctn is important for GnRH-mediated cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

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Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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Gonadotropin-releasing hormone (GnRH) receptor expression is often elevated in ovarian cancer, but its potential role in ovarian cancer metastasis has just begun to be revealed. Cadherin switching is a crucial step during tumorigenesis, particularly in metastasis. Here, we showed that GnRH is an inducer of E-to P-cadherin switching, which is reminiscent of that seen during ovarian tumor progression. Overexpression of P-cadherin significantly enhanced, whereas knockdown of P-cadherin reduced migration and invasion regardless of E-cadherin expression, suggesting that inappropriate expression of P-cadherin contributes to the invasive phenotype. These effects of P-cadherin were mediated by activation of the Rho GTPases, Rac1, and Cdc42, through accumulation of p120 catenin (p120 ctn ) in the cytoplasm. The use of p120 ctn small interfering RNA or chimeric cadherin construct to inhibit p120 ctn expression and cytoplasmic localization, respectively, resulted in significant inhibition of cell migration and invasion, with a concomitant reduction in Rac1 and Cdc42 activation, confirming that the effect was p120 ctn specific. Similarly, the migratory/invasive phenotype could be reversed by expression of dominant-negative Rac1 and Cdc42. These results identify for the first time cadherin switching and p120 ctn signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer.

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Section: Resultsmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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“…Choi et al (2006) have recently shown that gonadotrophins follicle-stimulating hormone and luteinizing hormone (FSH and LH) are able to reduce the levels of GnRH II but not GnRH I mRNA in ovarian surface epithelium and cancer cell lines. Gonadotrophin treatment also reduced the expression of the type I GnRHIR in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Binding of each may stabilise different receptor active conformations and allow ligand-specific selective signalling. Silencing of GnRHIR in ovarian cancer cells has certainly been shown to reverse the antiproliferative effects of GnRH II (Kim et al 2006). In contrast, Grundker et al (2004) working in ovarian and endometrial cells have reported that the GnRHIR is not required for the inhibitory effects of GnRH II.…”

Section: Discussionmentioning

confidence: 99%

Expression of GnRH type II is regulated by the androgen receptor in prostate cancer

Darby

Stockley²,

Khan³

et al. 2007

Endocr Relat Cancer

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GnRH II has important functional effects in steroid hormone-dependent tumours. Here we investigated the expression and regulation of GnRH II in prostate cancer. GnRH II protein was equally expressed in benign (73%) and malignant (78%) biopsies studied in a prostate tissue microarray (PZ0.779). There was no relationship between expression and clinical parameters in the cancer cohort. GnRH II was, however, significantly reduced in tumour biopsies following hormone ablation. This was further investigated in a prostate xenograft model where androgens increased GnRH II levels, while their withdrawal reduced it. In cell lines, we confirmed high levels of GnRH II in androgen receptor (AR)-positive LNCaP cells but low levels in AR-negative PC3 cells. In LNCaP cells, GnRH II induction by androgens was blocked by the AR inhibitor casodex, but not by cycloheximide treatment. Sequence analysis subsequently revealed a putative androgen response element in the upstream region of the GnRH II gene and direct interaction with the AR was confirmed in chromatin immunoprecipitation experiments. Finally, to test whether the effects of GnRH II were dependent on AR expression, LNCaP and PC3 cells were exposed to exogenous peptide. In both cell lines, GnRH II inhibited cell proliferation and migration, suggesting that its function is independent of AR status. These results provide evidence that GnRH II is widely expressed in prostate cancer and is an ARregulated gene. Further studies are warranted to characterise the effects of GnRH II on prostate cancer cells and investigate its potential value as a novel therapy.

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“…Since its discovery, w1000 GnRH analogues have been identified and widely studied (Conn & Crowley 1994, Cheung et al 2006. Besides its well-known endocrine function, GnRH may directly regulate some extrapituitary reproductive tissues such as endometrium, ovary and placenta (Islami et al 2001, Chou et al 2003, Grundker et al 2004, Kim et al 2006. Recent studies revealed that both GnRH and GnRH receptors are expressed in the human endometrium and endometrial cancer.…”

Section: Introductionmentioning

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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Mechanism of gonadotropin-releasing hormone (GnRH)-I and -II-induced cell growth inhibition in ovarian cancer cells: role of the GnRH-I receptor and protein kinase C pathway

Cited by 58 publications

References 41 publications

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Expression of GnRH type II is regulated by the androgen receptor in prostate cancer

GnRH signaling in intrauterine tissues

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