Abdelrahim Maen, Baker Cheryl H, Abbruzzese James L, Sheikh-Hamad David, Liu Shengxi, Cho Sung Dae, Yoon Kyungsil, Safe Stephen
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Cancer Res. 2007 Apr 1;67(7):3286-94. doi: 10.1158/0008-5472.CAN-06-3831.
Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagen-coated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer.
血管内皮生长因子受体-1（VEGFR1）在癌细胞系和肿瘤中表达，在胰腺癌细胞和结肠癌细胞中，VEGFR1的激活与肿瘤迁移和侵袭性增加有关。托芬那酸是一种非甾体抗炎药，可降低Panc-1和L3.6pl胰腺癌细胞中Sp蛋白的表达，同时伴随着VEGFR1蛋白和mRNA的减少，以及用含有VEGFR1启动子插入片段的构建体（pVEGFR1）转染的细胞中荧光素酶活性的降低。在用针对Sp1、Sp3和Sp4的小干扰RNA转染的胰腺癌细胞中也获得了类似的结果，并且这三种蛋白均与VEGFR1启动子中富含GC的元件结合。这些结果表明VEGFR1受Sp蛋白调控，并且托芬那酸处理可降低这种关键血管生成因子的表达。此外，在Panc-1细胞中的体外研究表明，托芬那酸也可抑制VEGFB激活VEGFR1以增加丝裂原活化蛋白激酶1/2磷酸化及细胞在胶原包被平板上的迁移。因此，靶向降解Sp蛋白对于抑制胰腺癌中的VEGFR1及相关血管生成反应非常有效。
