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http://dx.doi.org/10.14348/molcells.2016.2243

Salubrinal-Mediated Upregulation of eIF2α Phosphorylation Increases Doxorubicin Sensitivity in MCF-7/ADR Cells  

Jeon, Yong-Joon (Department of Biological Sciences, Konkuk University)
Kim, Jin Hyun (Department of Biological Sciences, Konkuk University)
Shin, Jong-Il (Department of Biological Sciences, Konkuk University)
Jeong, Mini (Department of Biological Sciences, Konkuk University)
Cho, Jaewook (Department of Biological Sciences, Konkuk University)
Lee, Kyungho (Department of Biological Sciences, Konkuk University)
Publication Information
Molecules and Cells / v.39, no.2, 2016 , pp. 129-135 More about this Journal
Abstract
Eukaryotic translation initiation factor 2 alpha ($eIF2{\alpha}$), which is a component of the eukaryotic translation initiation complex, functions in cell death and survival under various stress conditions. In this study, we investigated the roles of $eIF2{\alpha}$ phosphorylation in cell death using the breast cancer cell lines MCF-7 and MCF-7/ADR. MCF-7/ADR cells are MCF-7-driven cells that have acquired resistance to doxorubicin (ADR). Treatment of doxorubicin reduced the viability and induced apoptosis in both cell lines, although susceptibility to the drug was very different. Treatment with doxorubicin induced phosphorylation of $eIF2{\alpha}$ in MCF-7 cells but not in MCF-7/ADR cells. Basal expression levels of Growth Arrest and DNA Damage 34 (GADD34), a regulator of $eIF2{\alpha}$, were higher in MCF-7/ADR cells compared to MCF-7 cells. Indeed, treatment with salubrinal, an inhibitor of GADD34, resulted in the upregulation of $eIF2{\alpha}$ phosphorylation and enhanced doxorubicin-mediated apoptosis in MCF-7/ADR cells. However, MCF-7 cells did not show such synergic effects. These results suggest that dephosphorylation of $eIF2{\alpha}$ by GADD34 plays an important role in doxorubicin resistance in MCF-7/ADR cells.
Keywords
$eIF2{\alpha}$ phosphorylation; ER stress; GADD34; MCF-7/ADR cells; doxorubicin resistance;
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