Inhibition of MEK/ERK signaling induces apoptosis of acute myelogenous leukemia cells via inhibition of eukaryotic initiation factor 4E-binding protein 1 and down-regulation of Mcl-1

Apoptosis. 2010 Jul;15(7):795-804. doi: 10.1007/s10495-010-0483-y.

Abstract

We previously showed that the MEK inhibitor AZD6244 induced apoptosis in acute myelogenous leukemia (AML) HL60 cells. However, the mechanisms of AZD6244 to induce apoptosis remain to be fully elucidated. This study found that exposure of HL60 cells to AZD6244 down-regulated the levels of phosphor (p)-4E-binding protein 1 (4E-BP1), a substrate of mammalian target of rapamycin complex 1 (mTORC1), and anti-apoptotic protein Mcl-1. On the other hand, exposure of EOL-1 and MOLM13 cells to AZD6244 failed to induce apoptosis and levels of p-4E-BP1 and Mcl-1 were not down-regulated in these cells. These observations prompted us to hypothesize that down-regulation od 4E-BP1 and Mcl-1 might play an important role in AZD6244-mediated apoptosis. As expected, down-regulation of 4E-BP1 by an siRNA sensitized EOL-1 cells to AZD6244-mediated apoptosis in parallel with down-regulation of Mcl-1. Moreover, we found that blockade of mTORC1 by RAD001 synergistically enhanced the action of AZD6244 in leukemia cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Apoptosis*
  • Benzimidazoles / pharmacology*
  • Cell Cycle / drug effects
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Everolimus
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Female
  • HL-60 Cells
  • Humans
  • Leukemia, Promyelocytic, Acute / enzymology*
  • Leukemia, Promyelocytic, Acute / metabolism
  • Leukemia, Promyelocytic, Acute / pathology
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / genetics
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors

Substances

  • AZD 6244
  • Adaptor Proteins, Signal Transducing
  • Benzimidazoles
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors
  • Everolimus
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Sirolimus