GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors.
GnRH receptors (GnRH-R) have been found in various malignancies, including prostate cancer (PCa). They mediate the direct antitumor effects of GnRH analogs. Nevertheless, few reports concern drug-induced modulation of GnRH-R levels. In this study, we investigated GnRH-R expression in androgen-sensitive (LNCaP) and -insensitive (PC-3) PCa cells treated for 4 and 6 days with a GnRH agonist (Leuprorelin acetate, LA, 10(-11) or 10(-6) M), Dihydrotestosterone (DHT, 10(-9) M), Cyproterone acetate (CA, 10(-7) M), and Epidermal growth factor (EGF, 10 ng/ml), either alone or combined. The RT-PCR analysis showed no variation in GnRH-R mRNA levels of both treated LNCaP and PC-3 cells. On the contrary, immunoblotting indicated that in LNCaP and PC-3 cells, LA upregulated membrane GnRH-R expression (up to 92%). In androgen-sensitive cells, DHT induced a GnRH-R increase (up to 119%) always comparable to that occurring in the presence of CA. GnRH-R upregulation by LA/DHT or CA/DHT association was similar to that promoted by the single agents. In PC-3 cells, EGF upregulated GnRH-R (up to 110%). A prolonged treatment (for 12 days) determined a greater EGF-induced increase in GnRH-R levels (142%). Lower (or no) receptor enhancement occurred when LA and EGF were associated. Our findings indicate that LA post-transcriptionally upregulates its own membrane receptor in androgen-sensitive and -insensitive PCa cells, counteracting the receptor enhancement produced by DHT and EGF. The effects, obtained with a relatively long and continuous treatment, may have implications in the choice of therapy modality with GnRH analogs and may render the receptor a novel therapeutic target, particularly in hormone-refractory PCa.
Angelucci
Cristiana
C
Institute of Histology and Embryology, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168, Rome, Italy. cristiana.angelucci@rm.unicatt.it
Lama
Gina
G
Iacopino
Fortunata
F
Ferracuti
Silvia
S
Bono
Aldo V
AV
Millar
Robert P
RP
Sica
Gigliola
G
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017373:Cyproterone Acetate / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D016729:Leuprolide / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; C484844:GNRHR protein, human; D012333:RNA, Messenger; D011966:Receptors, LHRH; D013196:Dihydrotestosterone; D017373:Cyproterone Acetate; D016729:Leuprolide