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Glioblastoma multiforme is the most common primary brain tumor and one ofthe most aggressive types of cancer in adults. Survival signaling and apoptosisresistance are hallmarks of malignant glioma cells. However, recent studies haveshown that other types of cell death such as autophagy can be induced in malignantglioma cells. This suggests that stimulation of this process may be explored innew therapeutic strategies against glioblastoma multiforme. Protein kinase CK2is a highly conserved and constitutively active enzyme that promotes numerouscellular processes such as survival, proliferation and differentiation. CK2 hasbeen found elevated in several malignancies including brain tumors, and to conferresistance against chemotherapeutic agents and apoptotic stimuli. Recently, wehave shown that the siRNA-mediated downregulation of CK2 leads to cell death inDNA-PK-proficient human glioblastoma cells. We show, here, that lack of CK2 resultsin significant induction of autophagic cell death in two human glioblastoma celllines, M059K and T98G, as indicated by the positive staining of cells with theacidotropic dye acridine orange, and the specific recruitment of microtubule-associatedprotein 1 light chain 3 (LC3) to autophagosome membranes. Induction of autophagyis accompanied by CK2-dependent decreased phosphorylation of p70 ribosomal S6and AKT kinases and significantly reduced expression levels of Raptor. In contrast,phosphorylation and activity levels of ERK1/2 are enhanced suggesting an inhibitionof the PI3K/AKT/mTORC1 and activation of the ERK1/2 pathways. Furthermore, siRNA-mediatedsilencing of CK2 results in increased mitochondrial superoxide production in bothglioblastoma cell lines. However, mitochondrial reactive oxygen species releasecorrelates with induction of autophagy only in T98G cells. Taken together, ourfindings identify CK2 as a novel component of the autophagic machinery and underlinethe potential of its downregulation to kill glioblastoma cells by overcoming theresistance to multiple anticancer agents.

international journal of oncology

Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells