Leuprorelin acetate affects ERK1/2 activity in prostate cancer cells.
The mechanisms by which a GnRH analogue, leuprorelin acetate (LA), antagonizes the mitogenic effect of dihydrotestosterone (DHT) or epidermal growth factor (EGF) in prostate cancer cells is poorly understood. The mitogen-activated protein kinase system has a central role in growth regulation and, for this reason, we investigated the involvement of the extracellular signal-regulated kinase (ERK1/2) pathway in the response of both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells to LA alone or combined with EGF or DHT. The evaluation of ERK activation was performed by using Western blot analysis and immunocytochemistry. EGF specifically induced ERK1/2 activity in both models and this effect was counteracted by an inhibitor of EGF-receptor phosphorylation. The addition of LA produced an appreciable reduction of ERK phosphorylation promoted by EGF in LNCaP cells, while it generally determined an increase in ERK activity in androgen-unresponsive PC-3 cells. The slight ERK activation induced by DHT in LNCaP cells was counteracted by LA and this effect was evident only by immunocytochemistry. Our findings suggest that the antiproliferative effect of LA in prostate cancer cells stimulated by hormones and growth factors may be, at least in part, mediated by the reduction of ERK1/2 activation in LNCaP cells and linked to the unexpected increase of this activity produced by the analogue in PC-3 cells.
Iacopino
Fortunata
F
Istituto di Istologia ed Embriologia, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Lama
Gina
G
Angelucci
Cristiana
C
Sica
Gigliola
G
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016729:Leuprolide / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; D013196:Dihydrotestosterone; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016729:Leuprolide