Genua Marco, Pandini Giuseppe, Sisci Diego, Castoria Gabriella, Maggiolini Marcello, Vigneri Riccardo, Belfiore Antonino
Endocrinology, Department of Internal Medicine and Medical Specialties, University of Catania, Catania, Italy.
Cancer Res. 2009 Sep 15;69(18):7270-7. doi: 10.1158/0008-5472.CAN-09-0088. Epub 2009 Sep 8.
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.
胰岛素样生长因子-I受体（IGF-IR）的过表达可能在前列腺癌进展中发挥作用。我们之前发现，在前列腺癌细胞中，雄激素和雌激素均可通过非基因组途径上调IGF-IR。我们现在表明，在前列腺癌细胞中，用雄激素或雌激素刺激可通过诱导环磷酸腺苷反应元件结合蛋白（CREB）激活来上调IGF-IR。在雄激素受体（AR）阳性的LNCaP细胞中，两种性类固醇均以剂量依赖的方式使CREB在Ser(133)位点磷酸化，而在AR阴性的PC3细胞中只有雌激素能使CREB磷酸化。CREB磷酸化涉及c-Src依赖的细胞外信号调节激酶1/2激活，但不涉及蛋白激酶A、蛋白激酶C或钙调蛋白依赖性激酶II，并且在转染了不定位到细胞核的AR或雌激素受体突变体的细胞中也会发生。CREB沉默消除了IGF-IR的上调和启动子激活。我们还表明，CREB与IGF-IR启动子区域结合，并在IGF-IR启动子的5'-非翻译区片段中鉴定出相关的CREB结合位点。总之，我们描述了一种由性类固醇通过非基因组信号诱导CREB激活从而上调IGF-IR及其启动子活性的新机制。
