Role of Cyclic AMP Response Element-Binding Protein in Insulin-like Growth Factor-I Receptor Up-regulation by Sex Steroids in Prostate Cancer Cells
Role of Cyclic AMP Response Element-Binding Protein in Insulin-like Growth Factor-I Receptor Up-regulation by Sex Steroids in Prostate Cancer Cells
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DOI：
10.1158/0008-5472.can-09-0088
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Belfiore, Antonino
中科院分区：
文献类型：
--
作者：
Genua, Marco;Pandini, Giuseppe;Belfiore, Antonino
胰岛素样生长因子- 1受体（IGF-IR）过表达可能在前列腺癌的进展中起作用。我们之前发现，在前列腺癌细胞中，雄激素和雌激素通过非基因性途径上调IGF-IR。我们现在表明，在前列腺癌细胞中，雄激素或雌激素刺激通过诱导环AMP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，两种性类固醇都以剂量依赖的方式磷酸化Ser（133）位点的CREB，而在AR阴性的PC3细胞中，只有雌激素磷酸化CREB。CREB磷酸化涉及C - src依赖性细胞外信号调节激酶1/2活化，但不涉及蛋白激酶A、蛋白激酶C或钙调素依赖性激酶II，也发生在转染AR或雌激素受体突变体的细胞中，这些突变体不定位于细胞核。CREB沉默消除了IGF-IR上调和启动子激活。我们还发现CREB与IGF-IR启动子区域结合，并在IGF-IR启动子的5'-未翻译区片段上鉴定了相关的CREB结合位点。总之，我们描述了一个新的机制，IGF-IR上调和启动子活性通过CREB激活，由性类固醇诱导，通过非基因性信号传导。[癌症研究2009；69 (18): 7270 - 7]
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. [Cancer Res 2009;69(18):7270-7]