title: Salubrinal-Mediated Upregulation of eIF2α Phosphorylation Increases Doxorubicin Sensitivity in MCF-7/ADR Cells.
abstract: Eukaryotic translation initiation factor 2 alpha (eIF2α), 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 eIF2α 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 eIF2α 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 eIF2α, 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 eIF2α 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 eIF2α by GADD34 plays an important role in doxorubicin resistance in MCF-7/ADR cells.
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
authors.forename: Yong-Joon
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Shin
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
authors.forename: Mini
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
authors.forename: Jaewook
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 05029, Korea ; Korea Hemp Institute, Konkuk University, Seoul 05029, Korea.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Lee
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D015852:Eukaryotic Initiation Factor-2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D000903:Antibiotics, Antineoplastic; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D004317:Doxorubicin; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D013890:Thiourea
keywords: ER stress; GADD34; MCF-7/ADR cells, doxorubicin resistance; eIF2α phosphorylation