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 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.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Roberta M
RM
Moretti
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Marina
M
Montagnani Marelli
Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, Morristown, New Jersey, United States of America.
Deanne M
DM
Taylor
Drug Discovery and Translational Research, Shire Rare Diseases Unit, Lexington, Massachusetts, United States of America.
Paolo G V
PG
Martini
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Monica
M
Marzagalli
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Patrizia
P
Limonta
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000077143:Docetaxel; D004357:Drug Synergism; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction; D043823:Taxoids / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C495901:TP53 protein, human; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000077143:Docetaxel; D007987:Gonadotropin-Releasing Hormone; C505407:CASP3 protein, human; D053148:Caspase 3