Deactivation of Signal Transducer and Activator of Transcription 3 Reverses Chemotherapeutics Resistance of Leukemia Cells via Down-Regulating P-gp

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.

Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

“…It is well documented that many transcription factors, such as Ap-1, NF-kB, Akt and STAT3 are involved in activation of MDR1 gene in various cancers [24,25,26,27,28,29]. STAT3 binds to the potential promoter region, +64 and +72 of MDR1 in myeloid leukemia.…”

STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

“…MDR1, a well-known ATP-dependent drug efflux pump, is responsible for decreased drug accumulation in multidrugresistant cells and often mediates resistance to drugs in lung and breast cancer (35)(36)(37). Inhibition of STAT3 can reverse drug resistance in leukemia (38). It has been reported that inhibiting IL-6 and EGFR signaling simultaneously results in a more effective way to control non-small-cell-lung-cancer proliferation, and inhibition of STAT3 activity can increase the sensitivity to tyrosine kinase inhibitors in head and neck cancer (39).…”

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

“…In a recent report, the COX-2 inhibitor SC236 and the nonsteroidal antiinflammatory drug indomethacin were shown to inhibit P-gp and MRP1 expression and thus to enhance doxorubicin cytotoxicity in a MDR hepatocellular carcinoma cell line (Ye et al, 2011). Another therapeutic target in MDR leukemia may be STAT3 signaling; a recent study showed that STAT3 was overexpressed in MDR K562/AO2 leukemia cells and inhibition of STAT3 activation resulted in down-regulation of MDR1 transcription and P-gp expression (Zhang et al, 2011c).…”