Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells

Hye Jin Jung, Yonghyo Kim, Junghwa Chang, Sang Won Kang, Jeong Hun Kim, Ho Jeong Kwon

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1117-1128
Number of pages12
JournalJournal of Molecular Medicine
Volume91
Issue number9
DOIs
Publication statusPublished - 2013 Sep 1

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Vascular Endothelial Growth Factor Receptor
Electron Transport Complex III
Carrier Proteins
Endothelial Cells
Reactive Oxygen Species
Neoplasms
Vascular Endothelial Growth Factor A
Protein Transport
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Inhibitors
Protein Subunits
Signal Transduction
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Jung, Hye Jin ; Kim, Yonghyo ; Chang, Junghwa ; Kang, Sang Won ; Kim, Jeong Hun ; Kwon, Ho Jeong. / Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells. In: Journal of Molecular Medicine. 2013 ; Vol. 91, No. 9. pp. 1117-1128.
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abstract = "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.",
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Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells. / Jung, Hye Jin; Kim, Yonghyo; Chang, Junghwa; Kang, Sang Won; Kim, Jeong Hun; Kwon, Ho Jeong.

In: Journal of Molecular Medicine, Vol. 91, No. 9, 01.09.2013, p. 1117-1128.

Research output: Contribution to journalArticle

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