title: ER stress signaling in ARPE-19 cells after inhibition of protein kinase CK2 by CX-4945.
abstract: Protein kinase CK2 is a critical factor for the survival of cells. It is overexpressed in many cancer cells and provides protection against apoptosis in these cells. Inhibition of CK2 kinase activity in various cancer cells leads to apoptosis, which makes CK2 an attractive target for cancer therapy. Little is, however, known about CK2 inhibition in non-cancerous cells. Using the human retinal pigment epithelial cell line ARPE-19, we analyzed the formation of reactive oxygen species (ROS) and the ER stress signaling pathway after CK2 inhibition with CX-4945. Following CK2 inhibition, we did not find any significant generation of ROS in neither ARPE-19 non-cancer cells nor in HCT116 cancer cells. We found an induction of the ER stress pathway including the activation of eIF2α and ATF4 in both cell types. This activation was sufficient for ARPE-19 cells to cope with the ER stress. Furthermore, in contrast to HCT116 cancer cells, there was no induction of the pro-apoptotic transcription factor CHOP and no induction of apoptosis in the ARPE-19 cells. Overexpression of CHOP, however, induced apoptosis in ARPE-19 cells indicating that this step in the ER stress pathway is abrogated in normal cells compared to cancer cell.
authors.affiliation: Medical Biochemistry and Molecular Biology, University of the Saarland, Building 44, D-66424 Homburg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Intemann
authors.affiliation: Medical Biochemistry and Molecular Biology, University of the Saarland, Building 44, D-66424 Homburg, Germany.
authors.forename: Nathaniel Edward Bennett
authors.initials: NE
authors.lastname: Saidu
authors.affiliation: Medical Biochemistry and Molecular Biology, University of the Saarland, Building 44, D-66424 Homburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schwind
authors.affiliation: Medical Biochemistry and Molecular Biology, University of the Saarland, Building 44, D-66424 Homburg, Germany. Electronic address: M.Montenarh@mx.uni-saarland.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Montenarh
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology*; D010619:Phenazines; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000096:biosynthesis
chemical_list: C497109:ATF4 protein, human; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D009287:Naphthyridines; D010619:Phenazines; D017382:Reactive Oxygen Species; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C555142:silmitasertib; D047390:Casein Kinase II
keywords: Apoptosis; CHOP; ER stress; Growth arrest; Protein kinase