Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner.
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 month...
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2014
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oai:doaj.org-article:d114c6204f474410bdcc7b54ab9932ea2021-11-18T08:23:53ZGonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner.1932-620310.1371/journal.pone.0093713https://doaj.org/article/d114c6204f474410bdcc7b54ab9932ea2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24722580/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Gonadotropin-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 docetaxel-resistant CRPC patients expressing a functional p53 protein.Roberta M MorettiMarina Montagnani MarelliDeanne M TaylorPaolo G V MartiniMonica MarzagalliPatrizia LimontaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e93713 (2014) |
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Medicine R Science Q Roberta M Moretti Marina Montagnani Marelli Deanne M Taylor Paolo G V Martini Monica Marzagalli Patrizia Limonta Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| description |
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 docetaxel-resistant CRPC patients expressing a functional p53 protein. |
| format |
article |
| author |
Roberta M Moretti Marina Montagnani Marelli Deanne M Taylor Paolo G V Martini Monica Marzagalli Patrizia Limonta |
| author_facet |
Roberta M Moretti Marina Montagnani Marelli Deanne M Taylor Paolo G V Martini Monica Marzagalli Patrizia Limonta |
| author_sort |
Roberta M Moretti |
| title |
Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| title_short |
Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| title_full |
Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| title_fullStr |
Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| title_full_unstemmed |
Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| title_sort |
gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/d114c6204f474410bdcc7b54ab9932ea |
| work_keys_str_mv |
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