Role of cyclic AMP response element-binding protein in insulin-like growth factor-I receptor up-regulation by sex steroids in prostate cancer cells

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,stim ulation 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,prot ein 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 upregulation and promoter activity by CREB activation,induced by sex steroids,through a nongenotropic signaling. ©2009 American Association for Cancer Research.