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. Our data demonstrate a role of STAT3 in regulation of mdr1 gene expression in myeloid leukemia and suggest that STAT3 may be a promising therapeutic target for overcoming MDR resistance in myeloid leukemia.
Highlights
Leukemia is the sixth most lethal cancer accounting for 4% of all cancers, and the most common childhood cancer accounting for 32.6% of all childhood cancers
signal transducer and activator of transcription 3 (STAT3) is highly activated in drug non-sensitive advanced tumors. All these findings suggested that STAT3 might be associated with Multidrug resistance (MDR) and their relation needed to be defined, and this study aimed at deciphering the potential role of STAT3 in chemotherapy resistance in leukemia
By using STAT3dependent luciferase reporter construct, we observed that higher STAT3 activity was shown in K562/A02 (Fig. 1D), which was consistent with the results of western blot
Summary
Leukemia is the sixth most lethal cancer accounting for 4% of all cancers, and the most common childhood cancer accounting for 32.6% of all childhood cancers. The overexpression of P-gp, encoded by the ATP Binding Cassette B1 (ABCB1, known as mdr1) gene, is considered as one of the major obstacles to successful cancer chemotherapy.[1] P-gp is a trans-membrane glycoprotein which reduces intracellular drug concentrations by pumping drugs out of the cells.[2] Numerous studies have confirmed that the expression of P-gp is an adverse prognostic factor for complete remission and survival in adult AML.[3,4] the efflux-pump modulators used in clinic have been proved disappointing This is at least to a certain extent because the fundamental molecular mechanisms driving MDR phenotype of leukemia cells remain obscure. The characterization of signaling pathways about MDR leukemia is very important for designing rational novel therapies
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