The Novel VEGF121-VEGF165 Fusion Attenuates Angiogenesis and Drug Resistance via Targeting VEGFR2-HIF-1α-VEGF165/Lon Signaling Through PI3K-AKT-mTOR Pathway
[ Vol. 16 , Issue. 3 ]
Jui-Ling Tsai, Yu-May Lee, Chien-Yuan Pan and Alan Yueh-Luen LeePages 275-286 (12)
Anti-angiogenesis therapy is one major approach of cancer therapies nowadays. Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drugresistance that results from adaptive mechanisms, such as intratumor hypoxia. To obtain a more efficient therapeutic response, we created and identified a novel chimeric fusion of VEGF121
, which was connected by Fc region of human IgG1 to enhance dimerization. We found that the treatment of VEGF121
chimeric protein reduces proliferation, migration, invasion, and tube formation in endothelial and/or cancer cells through competing VEGF165 homodimer in a paracrine and an autocrine manner. Furthermore, the fusion protein attenuated autocrine VEGFR2-HIF-1α-VEGF165
/Lon signaling through PI3KAKT- mTOR pathway in cancer cells. In conclusion, our data demonstrated that the chimeric VEGF121
arrests the tube formation of endothelial cells and interferes with tumor cell growth, migration and invasion, suggesting that it could be a potential drug as an angiogenesis antagonist in cancer therapy. The VEGF121
targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1α- VEGF165
/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy.
Anti-angiogenesis, drug resistance, hypoxia, lon, the chimeric fusion, VEGF121-VEGF165.
National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli 35053, Taiwan.
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