The Novel VEGF121-VEGF165 Fusion Attenuates Angiogenesis and Drug Resistance via Targeting VEGFR2-HIF-1α-VEGF165/Lon Signaling Through PI3K-AKT-mTOR Pathway

Author(s): Jui-Ling Tsai, Yu-May Lee, Chien-Yuan Pan, Alan Yueh-Luen Lee.

Journal Name: Current Cancer Drug Targets

Volume 16 , Issue 3 , 2016

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Abstract:

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 and VEGF165, which was connected by Fc region of human IgG1 to enhance dimerization. We found that the treatment of VEGF121-VEGF165 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-VEGF165 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-VEGF165 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.

Keywords: Anti-angiogenesis, drug resistance, hypoxia, lon, the chimeric fusion, VEGF121-VEGF165.

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Article Details

VOLUME: 16
ISSUE: 3
Year: 2016
Page: [275 - 286]
Pages: 12
DOI: 10.2174/156800961603160206125352
Price: $58

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