title: Doxorubicin induces atypical NF-κB activation through c-Abl kinase activity in breast cancer cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Sección XVI, Delegación Tlalpan, CP 14000, Mexico, DF, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Esparza-López
authors.forename: Heriberto
authors.initials: H
authors.lastname: Medina-Franco
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Escobar-Arriaga
authors.forename: Eucario
authors.initials: E
authors.lastname: León-Rodríguez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Zentella-Dehesa
authors.forename: María J
authors.initials: MJ
authors.lastname: Ibarra-Sánchez
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000068877:Imatinib Mesylate; D007700:Kinetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000072000:NF-KappaB Inhibitor alpha; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl
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