Signalling and anti-proliferative effects mediated by gonadotrophin-releasing hormone receptors after expression in prostate cancer cells using recombinant adenovirus

Franklin, JL; Hislop, James N.; Flynn, Andrea; McArdle, Craig A.

doi:10.1677/joe.0.1760275

Cited by 31 publications

(21 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data confirm and extend previous in vitro data obtained with transfected HEK293 cells, MCF-7, and PC3 cells (26,28,(32)(33)(34) and contribute some novel observations. Three independent clones of rat B35 neuroblastoma cells (B35-2b, B35-2, and B35-20) and a derivative of the human ovarian cancer cell line SKOV3 (SKOV3-4) were informative in in vitro and in vivo studies done in parallel with HEK293 [SCL60] cells (26,28).…”

Section: Discussionsupporting

confidence: 91%

“…1). The functional effects of setting different levels of GnRH receptor expression using recombinant DNA have hitherto been described only in in vitro studies using MCF-7 and PC3 cells (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, levels of GnRH receptor expression at the cell surface have been carefully titrated in MCF-7 and PC3 cells using an adenoviral vector. Cell-surface receptor level was shown to be a major influence on the extent of GnRH-mediated growth inhibition in vitro (33,34).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2008

View full text Add to dashboard Cite

Activation of gonadotropin-releasing hormone (GnRH) receptors inhibits proliferation of transformed cells derived from reproductive tissues and in transfected cell lines. Hence, GnRH receptors represent a therapeutic target for direct action of GnRH analogues on certain proliferating cells. However, more cell biological data are required to develop this particular application of GnRH analogues. Therefore, we compared the effects of GnRH receptor activation in transfected HEK293 cells (HEK293 [SCL60] ) with transfected human ovarian cancer cell lines SKOV3 and EFO21, human hepatoblastoma HepG2 cells, and rat neuroblastoma B35 cells. Marked differences in receptor levels, magnitude of inositol phosphate generation, and dynamics of inositol phosphate turnover occurred in the different cells. Activation of GnRH receptors, expressed at high or moderate levels, inhibited the growth of HEK293 [SCL60] and B35 cells, respectively. Western blotting detected markers of apoptosis [cleaved poly(ADP-ribose) polymerase, caspase-9] in HEK293 [SCL60] and B35 following treatment with 100 nmol/L D-Trp 6 -GnRH

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2008

View full text Add to dashboard Cite

show abstract

“…[DTrp] 6 GnRH, a stable GnRH analog (GnRH-a), epidermal growth factor (EGF), genistein (PTK inhibitor), LY294002, and protein A-Sepharose were obtained from Sigma Chemicals Co. (St. Louis, MO). GF109203X, PD098059, SB203580, AG1478, PP2, and wortmannin were purchased from Calbiochem (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Gonadotropin-Releasing Hormone Induces Apoptosis of Prostate Cancer Cells

et al. 2004

View full text Add to dashboard Cite

A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH 2 -terminal kinase (JNK) and inhibited by the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src-and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.

show abstract

“…GnRH receptors are overexpressed both in reproductive organ cancers and cancers unrelated to the reproductive system (Franklin et al, 2003). GnRH analogs exert specific GnRH receptor-mediated antiproliferative, antimitogenic, and antimetastatic activities on cancer cells (Marelli et al, 2007).…”

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

View full text Add to dashboard Cite

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

show abstract

Signalling and anti-proliferative effects mediated by gonadotrophin-releasing hormone receptors after expression in prostate cancer cells using recombinant adenovirus

Abstract: Gonadotrophin-releasing hormone receptors (GnRH-Rs) are found in cancers of reproductive tissues, including those of the prostate, and gonadotrophin-releasing hormone (GnRH) can inhibit growth of cell lines derived from such cancers. Although pituitary and extra-pituitary

Cited by 31 publications

References 37 publications

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

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

Gonadotropin-Releasing Hormone Induces Apoptosis of Prostate Cancer Cells

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

Contact Info

Product

Resources

About