Luteinizing hormone-releasing hormone agonists interfere with the stimulatory actions of epidermal growth factor in human prostatic cancer cell lines, LNCaP and DU 145.
LH-releasing hormone (LHRH) agonists exert a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines. The present studies were aimed at clarifying whether these compounds might exert their antiproliferative action by interfering with the stimulatory action of epidermal growth factor (EGF). To this purpose, the effects of a LHRH agonist (Zoladex, LHRH-A) on the mitogenic action of EGF, on some of the EGF-activated intracellular signaling mechanisms (tyrosine phosphorylation of the 170-kDa EGF receptor, and c-fos protooncogene expression), as well as on the concentration of EGF receptors have been evaluated. These studies have been performed in both LNCaP and DU 145 cells. The results obtained show that in LNCaP cells, LHRH-A counteracts the mitogenic action of EGF, completely abrogates EGF-induced c-fos expression, and significantly reduces the concentration of EGF-binding sites. The EGF-activated tyrosine phosphorylation of the EGF receptor is not affected by LHRH-A in LNCaP cells. In DU 145 cells, LHRH-A antagonizes the proliferative action of EGF, inhibits the tyrosine phosphorylation of the EGF receptor induced by EGF, and significantly reduces the number of EGF-binding sites. In these cells, LHRH-A is not able to modify the increased expression of c-fos that follows the treatment with EGF. These data suggest that LHRH agonists may inhibit the proliferation of human prostatic tumor cells by interfering with the stimulatory actions of EGF. The intracellular mechanism of action of these compounds appears to differ in androgen-dependent LNCaP and androgen-independent DU 145 cells.
Moretti
R M
RM
Department of Endocrinology, Center for Endocrinological Oncology, Milan, Italy.
Marelli
M M
MM
Dondi
D
D
Poletti
A
A
Martini
L
L
Motta
M
M
Limonta
P
P
D002455:Cell Division / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D007987:Gonadotropin-Releasing Hormone; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors