Luteinizing hormone-releasing hormone agonists interfere with the mitogenic activity of the insulin-like growth factor system in androgen-independentprostate cancer cells

We have previously shown that LHRH agonists exert a direct and specific inh ibitory action on the proliferation of the androgen-independent DU 145 pros tate cancer cell line; however, the cellular mechanisms mediating this anti proliferative action are not well defined. It is well known that the insuli n-like growth factor (IGF) system plays a crucial role in the local regulat ion of the growth of androgen-independent prostate cancer. The present expe riments were performed to evaluate whether LHRH agonists might exert their antimitogenic effect by interfering with the activity of the locally expres sed IGF system. To this purpose, the effects of the LHRH agonist Zoladex (L HRH-A) on 1) the mitogenic action of IGF-I, 2) the tyrosine phosphorylation of type 1 IGF-I receptor (IGF-IR), 3) the concentration of IGF-IR, and 4) the secretion of IGF-binding protein-3 were studied. The results obtained s how that in DU 145 cells, LHRH-A 1) counteracts the mitogenic action of IGF -I in a dose-dependent manner, 2) prevents the IGF-I-induced tyrosine phosp horylation of the IGF-IR, 3) reduces the concentration of IGF-IR without af fecting its K-d value, and 4) does not affect the secretion of IGF-binding protein-3 in the conditioned medium from these cells. These data suggest that LHRH agonists may inhibit the proliferation of huma n androgen-independent prostate tumor cells by interfering with some of the cellular mechanisms mediating the stimulatory action of the IGF system.