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

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

Volume: 16 Issue: 3

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

Affiliation:

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

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.

Cite this article as:

Tsai Jui-Ling, Lee Yu-May, Pan Chien-Yuan and Lee Yueh-Luen Alan, The Novel VEGF₁₂₁-VEGF₁₆₅ Fusion Attenuates Angiogenesis and Drug Resistance via Targeting VEGFR2-HIF-1α-VEGF₁₆₅/Lon Signaling Through PI3K-AKT-mTOR Pathway, Current Cancer Drug Targets 2016; 16 (3) . https://dx.doi.org/10.2174/156800961603160206125352