Autocrine-inhibitory LHRH Loop Prostate Cancer Cell Line DU 145: Evidence for an Hormone (LHRH) Agonists on Human Androgen-independent Antiproliferative Effects of Luteinizing Hormone-releasing

The therapeutic options for the treatment of androgea-independent prostatic cancers are rather limited; this Is mainly because our under standing of the local mechanisms involved In the control of androgen independent proliferation of the tumor is stlH very poor. The present experlmeats have been performed to verify whether luteinizing hormone releasing hormone (LHRH) agonists may possess a direct effect on the growth of the human androgen-independeat prostate cancer cells DU 145 and whether a LHRH growth regulatory system may be present in these cells. The data have shown that two potent LHRII agonists (Zoladex and Buserelin) exert a significant and dose-dependent andproliferative action on DU 145 cells, after 4 days of treatment. The inhibitory action of Zoladex and Buserelin is completely counteracted by the simultaneous treatment of the cells with a potent LHRH antagonist, suggesting that the action of the LHRH agoaists may be mediated by specific receptors. This hypothesis has been confirmed by the demonstration that low-affinity binding sites for lasI@Buserelin are present on DU 145 cell membranes, particularly when cells are cultured in serum-free conditions. By using the reverse transcriptlon-polymerase chala reaction technique, in the pros eace of a pair of specificollgonucleotldeprimerscomplementaryto the human LHRH complementary DNA, it has been demonstrated that a mRNA for LHRH Is expressed In DU 145 cells. Taken together, these data seem to indicate that an autocrine/paracrine LHRH (or UIRH-llke) loop is present in androgea-independent prostate cancer cells, and may par ticipate in the regulation of tumor cell growth. To verify this hypothesis, DU145cellshavebeenculturedinserum-freeconditions, andtreatedwith a LHRHantagonistfor 4 days. The treatmentresultedin a significant increase of cell proliferation, suggesting an inhibitory role for the LHRH system in the local regulation of cell growth. In conclusion, these data demonstrate that: (a) LHRH agonists exert a specific antiproilferative action on the human androgen-independent DU 145 calls; (b) an autocrine/paracrine LHRH (or LIIRH.like) loop, which seems to be Inhibitory on cell proliferation, is expressed in DU 145 cells.