The Novel VEGF(121)-VEGF(165) Fusion Attenuates Angiogenesis and Drug Resistance via Targeting VEGFR2-HIF-1 alpha-VEGF(165)/Lon Signaling Through PI3K-AKT-mTOR Pathway

摘要

Anti-angiogenesis therapy is one major approach of cancer therapies nowadays. Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drug-resistance 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 VEGF(121) and VEGF(165), which was connected by Fc region of human IgG1 to enhance dimerization. We found that the treatment of VEGF(121)-VEGF(165) chimeric protein reduces proliferation, migration, invasion, and tube formation in endothelial and/or cancer cells through competing VEGF(165) homodimer in a paracrine and an autocrine manner. Furthermore, the fusion protein attenuated autocrine VEGFR2-HIF-1 alpha-VEGF(165)/Lon signaling through PI3K-AKT-mTOR pathway in cancer cells. In conclusion, our data demonstrated that the chimeric VEGF(121)-VEGF(165) 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 VEGF(121)-VEGF(165) targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1 alpha-VEGF(165)/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy.