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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

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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.

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Abbreviations

AML:

Acute myelogenous leukemia

MEK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

PI3K:

Phosphoinositide-3 kinase

mTOR:

Mammalian target of rapamycin

PBMCs:

Peripheral blood mononuclear cells

4E-BP1:

Eukaryotic initiation factor 4E-binding protein 1

FACS:

Flow cyctometry

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Acknowledgments

This work was supported in part by Grant-in-Aid from the Ministry of Education, Culture Sports, Science, and Technology of Japan (to T.I), The Kochi University President’s Discretionary Grant (to T.I), Takeda Science Foundation (to T.I), AstraZeneca Research Grant 2008 (to T.I), and Sagawa Foundation for Promotion of Cancer Research (to T.I). C.N. is grateful for a JSPS Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Oko-cho, Nankoku, Kochi, 783-8505, Japan

    Chie Nishioka, Takayuki Ikezoe, Jing Yang & Akihito Yokoyama

  2. Japanese Society for the Promotion of Science (JSPS), Chiyodaku, Tokyo, Japan

    Chie Nishioka

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  1. Chie Nishioka
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  2. Takayuki Ikezoe
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Correspondence to Takayuki Ikezoe.

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Nishioka, C., Ikezoe, T., Yang, J. et al. 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 15, 795–804 (2010). https://doi.org/10.1007/s10495-010-0483-y

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