Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145 : evidence for an autocrine-inhibitory LHRH loop

• Published in: Cancer research (Chicago, Ill.) Vol. 54; no. 15; pp. 4091 - 4095
• Main Authors: DONDI, D, LIMONTA, P, MORETTI, R. M, MARELLI, M. M, GARATTINI, E, MOTTA, M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-1994
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Buserelin - pharmacology; Cell Division - drug effects; Drug Screening Assays, Antitumor; General aspects; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Goserelin - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Prostatic Neoplasms - chemistry; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Rats; Rats, Sprague-Dawley; Receptors, LHRH - analysis; Tumor Cells, Cultured; Antineoplastic agent; Human; Cell proliferation; Agonist; Urinary system disease; Peptide hormone; Gonadotropin RH; Malignant tumor; Prostatic disease; In vitro; Hypothalamic hormone; Autocrine secretion; Regulation(control); Established cell line; Paracrine secretion; Inhibition; Hormone releasing factor; Male genital diseases; Prostate; Tumor cell
• ISSN: 0008-5472; 1538-7445

The therapeutic options for the treatment of androgen-independent prostatic cancers are rather limited; this is mainly because our understanding of the local mechanisms involved in the control of androgen-independent proliferation of the tumor is still very poor. The present experiments have been performed to verify whether luteinizing hormone-releasing hormone (LHRH) agonists may possess a direct effect on the growth of the human androgen-independent 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 LHRH agonists (Zoladex and Buserelin) exert a significant and dose-dependent antiproliferative 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 agonists may be mediated by specific receptors. This hypothesis has been confirmed by the demonstration that low-affinity binding sites for 125I-Buserelin are present on DU 145 cell membranes, particularly when cells are cultured in serum-free conditions. By using the reverse transcription-polymerase chain reaction technique, in the presence of a pair of specific oligonucleotide primers complementary to 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 LHRH-like) loop is present in androgen-independent prostate cancer cells, and may participate in the regulation of tumor cell growth. To verify this hypothesis, DU 145 cells have been cultured in serum-free conditions, and treated with a LHRH antagonist for 4 days. The treatment resulted in 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 antiproliferative action on the human androgen-independent DU 145 cells; (b) an autocrine/paracrine LHRH (or LHRH-like) loop, which seems to be inhibitory on cell proliferation, is expressed in DU 145 cells.