GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors

Angelucci, Cristiana; Lama, Gina; Iacopino, Fortunata; Ferracuti, Silvia; Bono, Aldo; Millar, Robert P.; Sica, Gigliola

doi:10.1007/s12020-009-9195-x

Cited by 16 publications

(22 citation statements)

References 48 publications

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“…(Leuschner et al, 2003) In this study, Leuschner et al reported that DHT-dependent upregulation of GnRH receptor expression (up to 119%) in GnRH receptor positive prostate cancer cells was responsible for this hypersensitivity (Angelucci et al, 2009). Receptor upregulation was observed to the same extent when cells were treated with a GnRH agonist and DHT (Angelucci et al, 2009). The higher sensitivity of DU145 cells to glycolipopeptides and triptorelin is plausibly due to the increased number of GnRH receptors in the presence of DHT.…”

Section: Impact Of Sex Steroids On the Antiproliferative Activitymentioning

confidence: 62%

“…These results were consistent with previous reports that showed a steroid-dependent antiproliferative activity of GnRH agonists. (Leuschner et al, 2003) In this study, Leuschner et al reported that DHT-dependent upregulation of GnRH receptor expression (up to 119%) in GnRH receptor positive prostate cancer cells was responsible for this hypersensitivity (Angelucci et al, 2009). Receptor upregulation was observed to the same extent when cells were treated with a GnRH agonist and DHT (Angelucci et al, 2009).…”

Section: Impact Of Sex Steroids On the Antiproliferative Activitymentioning

confidence: 64%

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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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Section: Impact Of Sex Steroids On the Antiproliferative Activitymentioning

confidence: 62%

Section: Impact Of Sex Steroids On the Antiproliferative Activitymentioning

confidence: 64%

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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“…In fact, antagonistic effects were observed on tumor cell growth as well as on the expression of PsA, MAP kinases, apoptosis-related genes and GnRH-R (22)(23)(24)(25)(26)(27)(28)(29). The molecular basis of the interference between DHT and LA is still unclear but conceivably could be ascribed to the analogue targeting of the androgen receptor (AR) signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In our experience, GnRH agonists are ineffective in regulating cell growth when used alone, but they counteract or suppress the stimulation of cell proliferation induced by estrogens in mammary and endometrial cancer cells (22)(23)(24) and by androgens or epidermal growth factor (EGF) in CaP cells (25). In the same CaP cells, we demonstrated the ability of the GnRH agonist, leuprorelin acetate (LA), to modulate the expression of various genes and/or proteins correlated with growth, differentiation and apoptosis and to up-regulate GnRH-R (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Leuprorelin acetate affects adhesion molecule expression in human prostate cancer cells

Angelucci

Lama²,

Iacopino³

et al. 2011

Int J Oncol

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Abstract. Reduced cell-cell adhesion allows malignant epithelial cells to invade the basal membrane and penetrate the stroma. This implies the potential of the cells to escape from the primary tumor as well as spreading ability. Herein, we investigated the effects of leuprorelin acetate (LA), a GnRH agonistic analogue, alone or in combination with dihydrotestosterone (DHT), on the expression of molecules involved in cell adhesion (E-cadherin, N-cadherin, α-, β-and γ-catenin) or in migration/invasion (c-met, CD44v6 and caveolin-1) in androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer (CaP) cells. We demonstrated by immunoblotting that, in LNCaP cells, molecules present in the adherens junctions (E-cadherin, α-, β-and γ-catenin) were expressed, while α-catenin was absent in PC-3 cells which expressed N-cadherin and c-met. In LNCaP cells, no changes in E-cadherin levels were produced by 10 -9 M DHT while LA (10 -11 or 10 -6 M) up-regulated the protein level (up to 26-30% after 48 h). In the same cells, β-and γ-catenin expression was enhanced either by DHT (24 and 20%, respectively) or LA (up to 18 and 40%, respectively), while α-catenin was not affected. Antagonistic effects were consistently observed between DHT and LA when the two hormones were jointly administered to the cells. Consistent results were obtained by immunocytochemistry. Co-immunoprecipitation analysis, used to verify the integrity of the LNCaP cell adhesion complex, demonstrated the association of E-cadherin with catenins. In PC-3 cells, adhesion molecule expression, analyzed by immunoblotting, was unaffected by LA, while a down-regulation of c-met (up to 28%) was observed after 24 h of treatment but which did not hold up over time (48-144 h). Our findings demonstrate the efficacy of LA in upregulating E-cadherin, β-and γ-catenin in LNCaP cells. This effect, that may be considered as another aspect of the direct antitumor activity of the GnRH analogue in hormone-dependent CaP cells, may contribute to maintenance/restoration of the normal tissue architecture counteracting the tumor cell spreading tendency.

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“…3 Some studies have elucidated a direct role for GnRH in prostate cancer cells. While there is still considerable debate, research indicates that GnRH agonist has antiproliferative effects on hormonesensitive and hormone-refractory human prostatic cancer cell lines.…”

Section: Gnrhr1 Silencing Blocks Antitumour Effect Of Gnrh Agonistmentioning

confidence: 99%

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

Kim

et al. 2011

J Int Med Res

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This study investigated the mechanism of action of a gonadotropin-releasing hormone (GnRH) agonist, leuprolide, on proliferation of the hormone-refractory prostate cancer cell line DU145, transfected with short hairpin RNA (shRNA), to reduce expression of the GNRHR1 gene (which encodes the GnRH type 1 receptor). DU145 cell proliferation in the presence of leuprolide (10 -9 and 10 -7 M) or control medium was measured before and after GnRHR1 knockdown. Reverse transcription-polymerase chain reaction and Western blot analysis were used to measure the degree of GNRHR1 silencing. DU145 cells treated with leuprolide (10 -9 and 10 -7 M) showed significant growth inhibition compared with control-treated DU145 cells. Transfection with GNRHR1-shRNA significantly decreased GNRHR1 expression at 48 h. DU145 cells transfected with silencing GNRHR1-shRNA showed normal growth patterns; however, there was no significant inhibition of proliferation of DU145 cells transfected with GNRHR1-shRNA compared with cells transfected with control-shRNA in response to leuprolide. These data demonstrated that the antiproliferative effect of leuprolide was mediated by the GnRHR1.

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GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors

Cited by 16 publications

References 48 publications

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

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

Leuprorelin acetate affects adhesion molecule expression in human prostate cancer cells

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

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