Doxorubicin induces atypical NF-κB activation through c-Abl kinase activity in breast cancer cells

J Cancer Res Clin Oncol. 2013 Oct;139(10):1625-35. doi: 10.1007/s00432-013-1476-3. Epub 2013 Jul 28.


Purpose: NF-κB transcription factor has been associated with cancer development and chemoresistance. We studied the signaling pathway activated by doxorubicin (DOX) leading to NF-κB activation in breast cancer cells.

Methods: NF-κB activity was evaluated by electrophoretic mobility shift in T47D, ZR75.30 and primary culture (MBCDF) from a ductal infiltrating carcinoma. Cell viability was measured by crystal violet. Western blotting was performed to check the expression and phosphorylation of IκBα Ser-32/36. c-Abl was inhibited with Imatinib or by overexpressing a dominant negative form of c-Abl (K290R).

Results: We found a correlation between sensitivity to DOX and amplitude of NF-κB activation. In cells least sensitive to DOX, NF-κB remained activated for longer time (T47D and MBCDF). The opposite effect was observed in cells sensitive to DOX (ZR75.30). DOX did not induce IκBα degradation or Ser-32/36 phosphorylation. Instead, there were modifications in the levels of IκBα tyrosine phosphorylation, suggesting an atypical NF-κB activation. In DOX-resistant cells, Imatinib treatment reduced IκBα tyrosine phosphorylation and NF-κB activity. The Imatinib-DOX combination significantly enhanced cell death of T47D and MBCDF breast cancer cells. Overexpression of c-Abl K290R in T47D and MBCDF cells reduced basal and DOX-induced NF-κB activation as well as IκBα tyrosine phosphorylation. In c-Abl K290R cells, DOX treatment did not mimic the combination Imatinib-DOX-induced cell death.

Conclusions: Inhibition of c-Abl inactivated IκBα/NF-κB pathway is associated with IκBα tyrosine phosphorylation in breast cancer cells. These results also raise the potential use of a combined therapy with Imatinib and DOX for breast cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • Benzamides / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • I-kappa B Proteins / metabolism
  • Imatinib Mesylate
  • Kinetics
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • Proteolysis
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Pyrimidines / pharmacology
  • Transcriptional Activation / drug effects


  • Antibiotics, Antineoplastic
  • Benzamides
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • NF-KappaB Inhibitor alpha
  • Doxorubicin
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-abl