自分泌信号
血管生成
旁分泌信号
PI3K/AKT/mTOR通路
癌症研究
蛋白激酶B
血管内皮生长因子
医学
信号转导
生物
细胞生物学
内科学
受体
血管内皮生长因子受体
作者
Jui-Ling Tsai,Yu‐May Lee,Chien‐Yuan Pan,Alan Yueh‐Luen Lee
出处
期刊:Current Cancer Drug Targets
[Bentham Science]
日期:2016-02-06
卷期号:16 (3): 275-286
被引量:15
标识
DOI:10.2174/156800961603160206125352
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 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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