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

Abstract

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 Ser(133) 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.

• Authors: Marco Genua, Giuseppe Pandini, Diego Sisci, Gabriella Castoria, Marcello Maggiolini, Riccardo Vigneri, Antonino Belfiore
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 18 Pg. 7270-7 (Sep 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19738069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Estrogen Receptor beta
• Metribolone
• Estradiol
• CREB-Binding Protein
• CREBBP protein, human
• Receptor, IGF Type 1

Topics

• CREB-Binding Protein (metabolism)
• Cell Line, Tumor
• Estradiol (pharmacology)
• Estrogen Receptor alpha (genetics, metabolism)
• Estrogen Receptor beta (genetics, metabolism)
• Humans
• Male
• Metribolone (pharmacology)
• Mutagenesis, Site-Directed
• Phosphorylation
• Promoter Regions, Genetic
• Prostatic Neoplasms (genetics, metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)
• Transfection
• Up-Regulation (drug effects)