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 IC 50 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.

Mithramycin A sensitizes therapy-resistant breast cancer stem cells toward genotoxic drug doxorubicin

“…To delineate the mechanisms underlying the enhanced chemoresistant behavior of bCSCs, we focused on Sp1 a transcription factor that regulates pivotal chemoresistance pathways. 22,23,30 Our results revealed a significant increase in the expression levels of Sp1 protein in CR primary tumors compared with CS primary tumors (Fig 3, A). Similarly, increased SP1 expression levels were observed in CR cell lines compared with their sensitive counterparts (Fig 3, B).…”

“…Recently, there has been renewed interest in the development of mithramycin A and its derivatives as anticancer agents because of their ability to specifically inhibit binding of Sp1 to GC-rich DNA, 27,30,31 and to downregulate numerous genes mediating proliferation, chemoresistance, invasion/ metastasis, and angiogenesis of cancer cells Q35 . [22][23][24][25][26][27] However, there is hardly any report describing the effect of mithramycin A in bCSCs.…”

“…[22][23][24] It also plays a critical role in various cellular processes associated AT A GLANCE COMMENTARY Saha S, et al Background Accumulating evidence suggests a major role of cancer stem cells (CSCs) in chemoresistance evoking the requirement of drugs that selectively target CSCs in combination with chemotherapy.…”

Influence of a survivin suppressor YM155 on the chemoresistance of canine histiocytic sarcoma cells

“…To assess protein expression of ABC transporter C2 and G2, Western blot analysis and immunocytochemistry were performed using antibodies specific for humans, mice and rabbits; however we were unable to identify cross-reactivity with these antibodies (data not shown). Some groups have demonstrated that activated specificity protein 1 and nuclear factor-κB enhanced the expression and activities of P-gp (Liu et al, 2010;Ke et al, 2013;Li et al, 2013). Our results suggest that suppressing chemoresistance through survivin-mediated transcription factors might extend therapeutic effects by adversely affecting DNA repair and drug elimination.…”

Upregulation of Multidrug Resistance-Associated Protein 1 by Allyl Isothiocyanate in Human Bronchial Epithelial Cell: Involvement of c-Jun N-Terminal Kinase Signaling Pathway

“…In addition, PI3K/Akt signaling pathway is another important intracellular signaling pathway which is also involved in the drug resistance of different types of human neoplasm cells [ 13 , 14 ]. LY294002, a PI3K-specific inhibitor, has been reported to reduce the activity of the MRP1 promoter by stimulating vascular endothelial growth factor (VEGF) [ 15 ]. In addition, treatment of K562 cell line with LY294002 or Akt siRNA downregulated P-glycoprotein (P-gp) and MRP1 expression [ 9 ].…”