Tan Clara, Cruet-Hennequart Severine, Troussard Armelle, Fazli Ladan, Costello Penny, Sutton Kym, Wheeler Jeff, Gleave Martin, Sanghera Jasbinder, Dedhar Shoukat
BC Cancer Agency, The Prostate Centre at Vancouver Hospital, and Department of Biochemistry and Molecular Biology, University of British Columbia, Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, V6H 3Z6 Canada.
Cancer Cell. 2004 Jan;5(1):79-90. doi: 10.1016/s1535-6108(03)00281-2.
We show that integrin-linked kinase (ILK) stimulates the expression of VEGF by stimulating HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner. In human prostate cancer cells, knockdown of ILK expression with siRNA, or inhibition of ILK activity, results in significant inhibition of HIF-1alpha and VEGF expression. In endothelial cells, VEGF stimulates ILK activity, and inhibition of ILK expression or activity results in the inhibition of VEGF-mediated endothelial cell migration, capillary formation in vitro, and angiogenesis in vivo. Inhibition of ILK activity also inhibits prostate tumor angiogenesis and suppresses tumor growth. These data demonstrate an important and essential role of ILK in two key aspects of tumor angiogenesis: VEGF expression by tumor cells and VEGF-stimulated blood vessel formation.
我们发现整合素连接激酶（ILK）通过以蛋白激酶B（PKB）/蛋白激酶B（Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）/FK506结合蛋白12-雷帕霉素相关蛋白（FRAP）依赖的方式刺激低氧诱导因子-1α（HIF-1α）蛋白表达，从而刺激血管内皮生长因子（VEGF）的表达。在人前列腺癌细胞中，用小干扰RNA（siRNA）敲低ILK表达或抑制ILK活性，会导致HIF-1α和VEGF表达受到显著抑制。在内皮细胞中，VEGF刺激ILK活性，抑制ILK表达或活性会导致VEGF介导的内皮细胞迁移、体外毛细血管形成及体内血管生成受到抑制。抑制ILK活性还会抑制前列腺肿瘤血管生成并抑制肿瘤生长。这些数据证明了ILK在肿瘤血管生成的两个关键方面发挥着重要且必不可少的作用：肿瘤细胞的VEGF表达以及VEGF刺激的血管形成。
