Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

J. A. McCubrey, S. L. Abrams, G. Ligresti, N. Misaghian, E. W T Wong, L. S. Steelman, J. Bäsecke, J. Troppmair, M. Libra, F. Nicoletti, S. Molton, M. McMahon, C. Evangelisti, A. M. Martelli

Research output: Contribution to journalArticlepeer-review

Abstract

A cytokine-dependent (FL5.12), drug-sensitive, p53 wild type (WT) and a doxorubicin-resistant derivative line (FL/Doxo) were used to determine the mechanisms that could result in drug resistance of early hematopoietic precursor cells. Drug resistance was associated with decreased p53 induction after doxorubicin treatment, which was due to a higher level of proteasomal degradation of p53. Dominant-negative (DN) p53 genes increased the resistance to chemotherapeutic drugs, MDM-2 and MEK inhibitors, further substantiating the role of p53 in therapeutic sensitivity. The involvement of signal transduction and apoptotic pathways was examined, as drug resistance did not appear to be due to increased drug efflux. Drug-resistant FL/Doxo cells had higher levels of activated Raf/MEK/ERK signaling and decreased induction of apoptosis when cultured in the presence of doxorubicin than drug-sensitive FL5.12 cells. Introduction of DN MEK1 increased drug sensitivity, whereas constitutively active (CA) MEK1 or conditionally active BRAF augmented resistance, documenting the importance of the Raf/MEK/ERK pathway in drug resistance. MEK inhibitors synergized with chemotherapeutic drugs to reduce the IC50. Thus the p53 and Raf/MEK/ERK pathways play key roles in drug sensitivity. Targeting these pathways may be effective in certain drug-resistant leukemias that are WT at p53.

Original languageEnglish
Pages (from-to)2080-2090
Number of pages11
JournalLeukemia
Volume22
Issue number11
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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