title: Downregulation of protein kinase CK2 induces autophagic cell death through             modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells.
abstract: Glioblastoma multiforme is the most common primary brain tumor and one of             the most aggressive types of cancer in adults. Survival signaling and apoptosis             resistance are hallmarks of malignant glioma cells. However, recent studies have             shown that other types of cell death such as autophagy can be induced in malignant             glioma cells. This suggests that stimulation of this process may be explored in             new therapeutic strategies against glioblastoma multiforme. Protein kinase CK2             is a highly conserved and constitutively active enzyme that promotes numerous             cellular processes such as survival, proliferation and differentiation. CK2 has             been found elevated in several malignancies including brain tumors, and to confer             resistance against chemotherapeutic agents and apoptotic stimuli. Recently, we             have shown that the siRNA-mediated downregulation of CK2 leads to cell death in             DNA-PK-proficient human glioblastoma cells. We show, here, that lack of CK2 results             in significant induction of autophagic cell death in two human glioblastoma cell             lines, M059K and T98G, as indicated by the positive staining of cells with the             acidotropic dye acridine orange, and the specific recruitment of microtubule-associated             protein 1 light chain 3 (LC3) to autophagosome membranes. Induction of autophagy             is accompanied by CK2-dependent decreased phosphorylation of p70 ribosomal S6             and AKT kinases and significantly reduced expression levels of Raptor. In contrast,             phosphorylation and activity levels of ERK1/2 are enhanced suggesting an inhibition             of the PI3K/AKT/mTORC1 and activation of the ERK1/2 pathways. Furthermore, siRNA-mediated             silencing of CK2 results in increased mitochondrial superoxide production in both             glioblastoma cell lines. However, mitochondrial reactive oxygen species release             correlates with induction of autophagy only in T98G cells. Taken together, our             findings identify CK2 as a novel component of the autophagic machinery and underline             the potential of its downregulation to kill glioblastoma cells by overcoming the             resistance to multiple anticancer agents.
authors.affiliation: Department of Nuclear Medicine, Odense University Hospital, 5000                     Odense, Denmark.
authors.forename: Birgitte B
authors.initials: BB
authors.lastname: Olsen
authors.forename: Tina H
authors.initials: TH
authors.lastname: Svenstrup
authors.forename: Barbara
authors.initials: B
authors.lastname: Guerra
mesh_terms: D001343:Autophagy / Q000235:genetics; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D047390:Casein Kinase II; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases