Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, South Korea.
J Mol Med (Berl). 2013 Sep;91(9):1117-28. doi: 10.1007/s00109-013-1049-6. Epub 2013 May 25.
Vascular endothelial growth factor (VEGF) signal transduction is involved in tumor angiogenesis, and the inhibition of this pathway is considered to be a powerful strategy for cancer therapy. We previously showed that small molecules targeting the ubiquinol-cytochrome c reductase binding protein (UQCRB), a subunit of mitochondrial complex III, in tumor cells suppress hypoxia-induced tumor angiogenesis. However, the mechanism by which UQCRB functioned remained unknown. In the present study, we demonstrate in endothelial cells (ECs) that UQCRB enhances VEGF receptor type 2 (VEGFR2) signaling by increasing the levels of mitochondrial reactive oxygen species (ROS). By contrast, terpestacin, a UQCRB targeting small molecule, blocked mitochondrial ROS-mediated VEGFR2 signaling pathways in ECs, thereby suppressing VEGF-dependent angiogenesis in vitro and in vivo. Furthermore, treatment with both terpestacin and bevacizumab, a VEGF signaling inhibitor, resulted in additive inhibition of tumor-induced angiogenesis both in vitro and in vivo. These data demonstrate that mitochondrial UQCRB positively regulates VEGFR2 signaling in ECs and the UQCRB targeting agent could be applied in new therapeutic approaches for human cancer.
Inhibiting angiogenesis has been a focus for anti-cancer strategies. Mitochondrial UQCRB enhances VEGFR2 signaling by increasing ROS in endothelial cells. UQCRB inhibitor blocks angiogenesis by suppressing mitochondrial ROS. Findings may provide a new therapeutic approach for human cancer.
血管内皮生长因子（VEGF）信号转导参与肿瘤血管生成，抑制该途径被认为是癌症治疗的有力策略。我们之前表明，针对线粒体复合物 III 亚单位泛醌-细胞色素 c 还原酶结合蛋白（UQCRB）的小分子在肿瘤细胞中抑制缺氧诱导的肿瘤血管生成。然而，UQCRB 发挥作用的机制尚不清楚。在本研究中，我们在血管内皮细胞（ECs）中证明，UQCRB 通过增加线粒体活性氧（ROS）的水平来增强血管内皮生长因子受体 2（VEGFR2）信号。相比之下，terpestacin，一种靶向 UQCRB 的小分子，阻断了 ECs 中线粒体 ROS 介导的 VEGFR2 信号通路，从而抑制了体外和体内的 VEGF 依赖性血管生成。此外，terpestacin 和 bevacizumab（一种 VEGF 信号抑制剂）联合治疗在体外和体内均导致肿瘤诱导的血管生成的相加抑制。这些数据表明，线粒体 UQCRB 正向调节 ECs 中的 VEGFR2 信号，并且靶向 UQCRB 的试剂可应用于人类癌症的新治疗方法。
抑制血管生成一直是抗癌策略的重点。线粒体 UQCRB 通过增加内皮细胞中的 ROS 来增强 VEGFR2 信号。UQCRB 抑制剂通过抑制线粒体 ROS 来阻断血管生成。研究结果可能为人类癌症提供新的治疗方法。
