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Role of Cyclic AMP Response Element–Binding Protein in Insulin-like Growth Factor-I Receptor Up-regulation by Sex Steroids in Prostate Cancer Cells

¹ Endocrinology, Department of Internal Medicine and Medical Specialties, University of Catania, Catania, Italy; ² Department of Pharmaco-Biology, University of Calabria, Cosenza, Italy; ³ Department of General Pathology, II University of Naples, Naples, Italy; and ⁴ Endocrinology, Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro, Italy

Requests for reprints: Antonino Belfiore, Department of Clinical and Experimental Medicine, University of Catanzaro, Campus Universitario, 88100 Catanzaro, Italy. Phone: 39-961-3697154; Fax: 39-961-3697408; E-mail: belfiore{at}unicz.it.

Key Words: IGF-IR • sex steroids • CREB • IGFs

Insulin-like growth factor-I receptor (IGF-IR) overexpression may play a role in prostate cancer progression. We found previously that, in prostate cancer cells, IGF-IR is up-regulated by both androgens and estrogens via a nongenotropic pathway. We now show that, in prostate cancer cells, stimulation with either androgens or estrogens up-regulates IGF-IR by inducing cyclic AMP response element–binding protein (CREB) activation. Both sex steroids phosphorylated CREB at Ser¹³³ in a dose-dependent manner in androgen receptor (AR)–positive LNCaP cells, whereas only estrogens phosphorylated CREB in AR-negative PC3 cells. CREB phosphorylation involved c-Src–dependent extracellular signal-regulated kinase 1/2 activation, but not protein kinase A, protein kinase C, or calmodulin-dependent kinase II, and occurred also in cells transfected with AR or estrogen receptor mutants that do not localize into the nucleus. CREB silencing abrogated IGF-IR up-regulation and promoter activation. We also showed that CREB binds to IGF-IR promoter region and identified the relevant CREB-binding site at the 5'-untranslated region fragment of IGF-IR promoter. In conclusion, we describe a novel mechanism of IGF-IR up-regulation and promoter activity by CREB activation, induced by sex steroids, through a nongenotropic signaling. [Cancer Res 2009;69(18):7270–7]