Gonadotropin-releasing hormone agonists reduce the migratory and the invasive behavior of androgen-independent prostate cancer cells by interfering with the activity of IGF-I.
Androgen-independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior. We have previously shown that GnRH agonists exert a direct and specific inhibitory action on the proliferation of androgen-independent prostate cancer cells (DU 145). These compounds mainly act by interfering with the mitogenic activity of growth factors, such as the insulin-like growth factor-I (IGF-I). The present experiments were performed to clarify whether GnRH agonists might also affect the migratory and the invasive behavior of androgen-independent prostate cancer cells and to define their mechanism of action. First we showed that the GnRH agonist Leuprolide reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane. Experiments were then performed to clarify whether the GnRH agonist might act by interfering with the pro-metastatic activity of IGF-I. We found that, in androgen-independent prostate cancer cells, Leuprolide: a) interferes with the IGF-I system (receptor protein expression and tyrosine-phosphorylation); b) abrogates the IGF-I-induced phosphorylation of Akt (a kinase previously shown by us to mediate the pro-metastatic activity of IGF-I in prostate cancer cells); c) counteracts the migration and the invasive activity of the cells stimulated by IGF-I; d) abolishes the effects of IGF-I on cell morphology, on actin cytoskeleton organization and on alphavbeta3 integrin expression/cellular localization. These data indicate that GnRH agonists, in addition to their well known antiproliferative effect, can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen-independent prostate cancer cells, expressing the GnRH receptor. GnRH agonists act by interfering with the pro-metastatic activity of the growth factor IGF-I.
Montagnani Marelli
Marina
M
Institute of Endocrinology, Center for Endocrinological Oncology, University of Milano, Milano, Italy.
Moretti
Roberta M
RM
Mai
Stefania
S
Procacci
Patrizia
P
Limonta
Patrizia
P
D000728:Androgens / Q000502:physiology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D016729:Leuprolide / Q000494:pharmacology*; D008297:Male; D008855:Microscopy, Electron, Scanning; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000648:ultrastructure
D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D007987:Gonadotropin-Releasing Hormone; D007334:Insulin-Like Growth Factor I; D016729:Leuprolide