Gonadotropin-releasing hormone (GnRH) receptors are expressed in prostate cancer, specifically in the most aggressive stage of the tumor (castration-resistant prostate cancer, CRPC) for which the standard treatment, docetaxel-based chemotherapy, can only improve the median survival time by few months. We previously showed that GnRH agonists exert an antitumor activity in CRPC cells; however, a link between GnRH receptors and the apoptotic machinery remains to be defined. Aim of this study was to evaluate whether, in CRPC cells, GnRH agonists might affect the expression/activity of apoptosis-related proteins and might sensitize, or resensitize, cancer cells to chemotherapeutics. We demonstrated that, in p53-positive DU145 cells, GnRH agonists: a) increase the expression of the proapoptotic protein Bax; this effect is mediated by the phosphorylation (activation) of p53, triggered by the p38 MAPK; b) potentiate the antiproliferative/proapoptotic activity of docetaxel; c) resensitize docetaxel-resistant cells to the antitumor activity of the cytotoxic drug. These data indicate that GnRH agonists sensitize and, more importantly, resensitize DU145 CRPC cells to chemotherapy in a p53- dependent manner. To confirm the crucial role of p53 in the activity of GnRH agonists, experiments were performed in p53- null PC3 cells. We found that GnRH agonists fail to increase Bax expression and do not potentiate the cytotoxic activity of docetaxel. These results may provide a rationale for novel combination treatment strategies, especially for docetaxelresistant CRPC patients expressing a functional p53 protein.

Gonadotropin-Releasing Hormone Agonists Sensitize, and Resensitize, Prostate Cancer Cells to Docetaxel in a p53-Dependent Manner / R.M. Moretti, M. Montagnani Marelli, D.M. Taylor, P.G.V. Martini, M. Marzagalli, P. Limonta. - In: PLOS ONE. - ISSN 1932-6203. - 9:4(2014 Apr), pp. e93713.1-e93713.12.

Gonadotropin-Releasing Hormone Agonists Sensitize, and Resensitize, Prostate Cancer Cells to Docetaxel in a p53-Dependent Manner

R.M. Moretti
Primo
;
M. Montagnani Marelli
Secondo
;
M. Marzagalli
Penultimo
;
P. Limonta
Ultimo
2014

Abstract

Gonadotropin-releasing hormone (GnRH) receptors are expressed in prostate cancer, specifically in the most aggressive stage of the tumor (castration-resistant prostate cancer, CRPC) for which the standard treatment, docetaxel-based chemotherapy, can only improve the median survival time by few months. We previously showed that GnRH agonists exert an antitumor activity in CRPC cells; however, a link between GnRH receptors and the apoptotic machinery remains to be defined. Aim of this study was to evaluate whether, in CRPC cells, GnRH agonists might affect the expression/activity of apoptosis-related proteins and might sensitize, or resensitize, cancer cells to chemotherapeutics. We demonstrated that, in p53-positive DU145 cells, GnRH agonists: a) increase the expression of the proapoptotic protein Bax; this effect is mediated by the phosphorylation (activation) of p53, triggered by the p38 MAPK; b) potentiate the antiproliferative/proapoptotic activity of docetaxel; c) resensitize docetaxel-resistant cells to the antitumor activity of the cytotoxic drug. These data indicate that GnRH agonists sensitize and, more importantly, resensitize DU145 CRPC cells to chemotherapy in a p53- dependent manner. To confirm the crucial role of p53 in the activity of GnRH agonists, experiments were performed in p53- null PC3 cells. We found that GnRH agonists fail to increase Bax expression and do not potentiate the cytotoxic activity of docetaxel. These results may provide a rationale for novel combination treatment strategies, especially for docetaxelresistant CRPC patients expressing a functional p53 protein.
Settore BIO/13 - Biologia Applicata
Settore BIO/09 - Fisiologia
apr-2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/234272
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