Vascular endothelial growth factor induces multidrug resistance-associated protein 1 overexpression through phosphatidylinositol-3-kinase/protein kinase B signaling pathway and transcription factor specificity protein 1 in BGC823 cell line  

作　　者：Juan Li Xiaojun Wu Jinling Gong Jing Yang Jiayan Leng Qiaoyun Chen Wenlin Xu 

机构地区：[1]The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, China

出　　处：《Acta Biochimica et Biophysica Sinica》2013年第8期656-663,共8页生物化学与生物物理学报（英文版）

摘　　要：Multidrug resistance （MDR） is one of the most important causes of chemotherapy failure and carcinoma recurrence. But the roles of the MDR-associated protein MRP1 in MDR remain poorly understood. Vascular endothelial growth factor （VEGF）, one of the most active and specific vascular growth factors, plays a significant role in prolifer- ation, differentiation, and metastasis of cancers. To explore the effect of VEGF on the expression of MRP1, we used re- combinant human VEGF to stimulate K562 and BGC-823 cell lines. Quantitative real-time polymerase chain reaction and western blot analysis showed that the expression of MRP1 at both mRNA and protein levels was increased. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyl tetrazolium bro- mide results also showed that VEGF significantly enhanced the ICso of the cells treated with adriamycin. To explore the underlying regulatory mechanisms, we constructed MRP1 promoter and the luciferase reporter gene recombinant vector. The luciferase reporter gene assay showed that the activity of the MRP1 promoter was markedly increased by VEGF stimulation, while LY294002, an inhibitor of the phosphatidylinositol-3-kinase （PI3K）/protein kinase B （Akt） signaling pathway, reduced this effect. Transcription factor specificity protein 1 （SP1） binding site mutation partially blocked the up-regulation of MRP1 promoter activity by VEGF. In summary, our results demonstrated that VEGF enhanced the expression of MRP1, and the PI3K/Akt signal- ing pathway and SP1 may be involved in this modulation.Multidrug resistance （MDR） is one of the most important causes of chemotherapy failure and carcinoma recurrence. But the roles of the MDR-associated protein MRP1 in MDR remain poorly understood. Vascular endothelial growth factor （VEGF）, one of the most active and specific vascular growth factors, plays a significant role in prolifer- ation, differentiation, and metastasis of cancers. To explore the effect of VEGF on the expression of MRP1, we used re- combinant human VEGF to stimulate K562 and BGC-823 cell lines. Quantitative real-time polymerase chain reaction and western blot analysis showed that the expression of MRP1 at both mRNA and protein levels was increased. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyl tetrazolium bro- mide results also showed that VEGF significantly enhanced the ICso of the cells treated with adriamycin. To explore the underlying regulatory mechanisms, we constructed MRP1 promoter and the luciferase reporter gene recombinant vector. The luciferase reporter gene assay showed that the activity of the MRP1 promoter was markedly increased by VEGF stimulation, while LY294002, an inhibitor of the phosphatidylinositol-3-kinase （PI3K）/protein kinase B （Akt） signaling pathway, reduced this effect. Transcription factor specificity protein 1 （SP1） binding site mutation partially blocked the up-regulation of MRP1 promoter activity by VEGF. In summary, our results demonstrated that VEGF enhanced the expression of MRP1, and the PI3K/Akt signal- ing pathway and SP1 may be involved in this modulation.

关 键 词：cancer VEGF MRP1 PI3K/AKT signalingpathway SP1 

分 类 号：Q78[生物学—分子生物学] S435.112.3[农业科学—农业昆虫与害虫防治]