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. Key message: 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.
Bibliographical noteFunding Information:
Acknowledgments We are grateful to Young-Guen Kwon for technical assistance with the Matrigel plug assay and Paul Schumacker, Natalie Ahn, and James Chen for critical comments. This study was partly supported by grants from the National Research Foundation of Korea funded by the Korean Government (MEST; 2009-0092964, 2010-0017984, 2012M3A9D1054520), the Translational Research Center for Protein Function Control, KRF (2009-0083522), the Center for Food and Drug Materials of Agriculture Science & Technology Development (PJ0079772012), Rural Development Administration, National R&D Program, Ministry of Health &Welfare (0620360-1), and the Brain Korea 21 Project, Republic of Korea.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery