Department of Radiation Oncology, Emory University, 1365 Clifton Road, NE, Suite CT-104, Atlanta, GA 30322, USA.
Mol Cancer Res. 2013 Aug;11(8):875-86. doi: 10.1158/1541-7786.MCR-12-0706. Epub 2013 May 1.
Cyclooxygenase-2 (COX-2) is linked to poor prognosis in patients with malignant gliomas. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. EGFR signaling, through activation of the p38-MAPK/PKC-δ/Sp1 cascade, plays an essential role in the regulation of COX-2 expression in glioma cells. Here, we report that Src kinase contributes upstream to this signaling cascade. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein increased after stimulation with EGF, although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (-2872/-2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 forms a cooperative interaction with Sp1 at the Sp1-binding site (-245/-240 relative to the start site) of the COX-2 promoter to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides a clearer understanding of the mechanistic basis for EGF induction of COX-2.
These data provide a guide for the evaluation of potential newer therapeutic targets that have relevance in this disease.
环氧化酶-2（COX-2）与恶性神经胶质瘤患者的预后不良有关。这些肿瘤中通常存在表皮生长因子受体（EGFR）的扩增/过表达。EGFR 信号通过激活 p38-MAPK/PKC-δ/Sp1 级联反应，在调节神经胶质瘤细胞中 COX-2 的表达中起着至关重要的作用。在这里，我们报告Src 激酶在该信号级联反应的上游起作用。此外，更详细的分析表明叉头框转录因子 FOXM1 参与了 EGF 依赖性 COX-2 诱导。尽管 FOXM1 蛋白在调节 COX-2 表达中的作用不依赖于这种增加，但在 EGF 刺激后，FOXM1 蛋白增加。虽然 COX-2 启动子的远端区域（相对于转录起始位点的-2872/-2539）存在一个传统的 FOXM1 反应元件，但这不是 EGF 依赖性 COX-2 诱导所必需的。相反，FOXM1 在 COX-2 启动子的 Sp1 结合位点（相对于起始位点的-245/-240）与 Sp1 形成协同相互作用，介导 EGF 诱导的 COX-2 表达。该新相互作用的定义为 EGF 诱导 COX-2 的机制基础提供了更清晰的理解。
这些数据为评估在这种疾病中具有相关性的潜在新型治疗靶标提供了指导。
