Deactivation of signal transducer and activator of transcription 3 reverses chemotherapeutics resistance of leukemia cells via down-regulating P-gp

PLoS One. 2011;6(6):e20965. doi: 10.1371/journal.pone.0020965. Epub 2011 Jun 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Antibiotics, Antineoplastic / pharmacology
  • Down-Regulation / drug effects
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / physiology*
  • Drug Resistance, Neoplasm / physiology*
  • Gene Expression Regulation, Leukemic
  • Genes, MDR
  • Humans
  • K562 Cells / drug effects
  • Leukemia / physiopathology*
  • Oligodeoxyribonucleotides / genetics
  • Oligodeoxyribonucleotides / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Oligodeoxyribonucleotides
  • STAT3 Transcription Factor
  • Doxorubicin