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Androgens Up-regulate the Insulin-like Growth Factor-I Receptor in Prostate Cancer Cells

¹ Dipartimento di Medicina Interna e di Medicina Specialistica, Cattedra di Endocrinologia, University of Catania, Ospedale Garibaldi, Catania, Italy; ² Department of Pediatrics, Oregon Health and Science University, Portland, Oregon; ³ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, Texas; and ⁴ Dipartimento di Medicina Sperimentale e Clinica, Cattedra di Endocrinologia, Policlinico Mater Domini, University of Catanzaro "Magna Graecia," Catanzaro, Italy

Requests for reprints: Antonino Belfiore, Dipartimento di Medicina Sperimentale e Clinica, Cattedra di Endocrinologia, Policlinico Mater Domini, University of Catanzaro "Magna Graecia," via T. Campanella 115, 88100 Catanzaro, Italy. Phone: 39-961-712-423; Fax: 39-961-772-748; E-mail: belfiore{at}unicz.it.

In this study, we show that androgens up-regulate insulin-like growth factor-I receptor (IGF-IR) expression and sensitize prostate cancer cells to the biological effects of IGF-I. Both dihydrotestosterone and the synthetic androgen R1881 induced an 6-fold increase in IGF-IR expression in androgen receptor (AR)–positive prostate cancer cells LNCaP. In accordance with IGF-IR up-regulation, treatment with the nonmetabolizable androgen R1881 sensitized LNCaP cells to the mitogenic and motogenic effects of IGF-I, whereas an IGF-IR blocking antibody effectively inhibited these effects. By contrast, these androgens did not affect IGF-IR expression in AR-negative prostate cancer cells PC-3. Reintroduction of AR into PC-3 cells by stable transfection restored the androgen effect on IGF-IR up-regulation. R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide). Two other AR antagonists, cyproterone acetate and OH-flutamide, were much less effective. Androgen-induced IGF-IR up-regulation was not dependent on AR genomic activity, because two AR mutants, AR-C619Y and AR-C574R, devoid of DNA binding activity and transcriptional activity were still able to elicit IGF-IR up-regulation in HEK293 kidney cells in response to androgens. Moreover, androgen-induced IGF-IR up-regulation involves the activation of the Src-extracellular signal-regulated kinase pathway, because it was inhibited by both the Src inhibitor PP2 and the MEK-1 inhibitor PD98059. The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action. Anti-androgen therapy may be only partially effective, or almost ineffective, in blocking important biological effects of androgens, such as activation of the IGF system.

Key Words: Androgen • IGF system • IGF-I receptor • Insulin receptor • Prostate cancer

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