title: 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.
abstract: 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 proliferation, differentiation, and metastasis of cancers. To explore the effect of VEGF on the expression of MRP1, we used recombinant 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 bromide results also showed that VEGF significantly enhanced the IC50 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 signaling pathway and SP1 may be involved in this modulation.
authors.affiliation: The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
authors.forename: Jinling
authors.initials: J
authors.lastname: Gong
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Jiayan
authors.initials: J
authors.lastname: Leng
authors.forename: Qiaoyun
authors.initials: Q
authors.lastname: Chen
authors.forename: Wenlin
authors.initials: W
authors.lastname: Xu
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D017931:DNA Primers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; C421109:multidrug resistance-associated protein 1
keywords: MRP1; PI3K/AKT signaling pathway; SP1; VEGF; cancer