RRC ID 38229
著者 Nishioka C, Ikezoe T, Yang J, Yokoyama A.
タイトル 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.
ジャーナル Apoptosis
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.
巻・号 15(7)
ページ 795-804
公開日 2010-7-1
DOI 10.1007/s10495-010-0483-y
PMID 20221697
MeSH 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
IF 4.543
引用数 27
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞