deactivation of signal transducer and activator of transcription 3 reverses chemotherapeutics resistance of leukemia cells via down-regulating p-gp信号传感器和催化剂的失活转录3逆转化疗耐药性的白血病细胞通过显示p-gp.pdfVIP

Deactivation of Signal Transducer and Activator of Transcription 3 Reverses Chemotherapeutics Resistance of Leukemia Cells via Down-Regulating P-gp 1,2,3 3 1 3 1 Xulong Zhang , Weihua Xiao , Lihua Wang , Zhigang Tian , Jian Zhang * 1 School of Pharmaceutical Sciences, Shandong University, Jinan, China, 2 Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China, 3 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China Abstract Multidrug resistance (MDR) caused by overexpression of p-glycoprotein is a major obstacle in chemotherapy of malignant cancer, which usually is characterized by constitutive activation of signal transducer and activator of transcription 3 (STAT3), but their relation between MDR and STAT3 remains unclear. Here, we showed that STAT3 was overexpressed and highly activated in adriamycin-resistant K562/A02 cells compared with its parental K562 cells. Blockade of activation of STAT3 by STAT3 decoy oligodeoxynucleotide (ODN) promoted the accumulation and increased their sensitivity to adriamycin by down-regulating transcription of mdr1 and expression of P-gp, which were further confirmed by using STAT3-specific inhibitor JSI-124. Inhibition of STAT3 could also decrease mdr1 promoter mediated luciferase expression by using mdr1 promoter luciferase reporter construct. Otherwise, activation of STAT3 by STAT3C improved mdr1 transcription and P-gp expression. The ChIP results demonstrated that STAT3 could bind to the potential promoter region of mdr1, and STAT3 decoy depressed the binding. Further mutation assay show +64,+72 region could be the STAT3 binding site.