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

  • Authors:
    • Birgitte B. Olsen
    • Tina H. Svenstrup
    • Barbara Guerra

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  • Published online on: September 21, 2012     https://doi.org/10.3892/ijo.2012.1635
  • Pages: 1967-1976

  • Copyright: © Olsen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.
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December 2012
Volume 41 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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  • Impact Factor: 4.5
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  • CiteScore: 9.6
  • CiteScore Rank: Q1: #66/404 Oncology
  • Source Normalized Impact per Paper (SNIP): 0.88
  • SCImago Journal Rank (SJR): 1.099
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Spandidos Publications style
Olsen BB, Svenstrup TH and Guerra B: Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells. Int J Oncol 41: 1967-1976, 2012.
APA
Olsen, B.B., Svenstrup, T.H., & Guerra, B. (2012). Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells. International Journal of Oncology, 41, 1967-1976. https://doi.org/10.3892/ijo.2012.1635
MLA
Olsen, B. B., Svenstrup, T. H., Guerra, B."Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells". International Journal of Oncology 41.6 (2012): 1967-1976.
Chicago
Olsen, B. B., Svenstrup, T. H., Guerra, B."Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells". International Journal of Oncology 41, no. 6 (2012): 1967-1976. https://doi.org/10.3892/ijo.2012.1635