title: The Novel VEGF121-VEGF165 Fusion Attenuates Angiogenesis and Drug Resistance via Targeting VEGFR2-HIF-1α-VEGF165/Lon Signaling Through PI3K-AKT-mTOR Pathway.
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.
authors.forename: Jui-Ling
authors.initials: JL
authors.lastname: Tsai
authors.forename: Yu-May
authors.initials: YM
authors.lastname: Lee
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Pan
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli 35053, Taiwan. alanylee@nhri.org.tw.
authors.forename: Alan Yueh-Luen
authors.initials: AY
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C546842:MTOR protein, human; C000588866:KDR protein, human