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.

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

“…17 However, the effect of CSNK2 on autophagy is controversial, because CSNK2 significantly inhibits autophagy induction in human glioblastoma cells (M059K and T98G). 36 In this study, we provide both in vitro and in vivo evidence demonstrating that ATG16L1 is a novel substrate of CSNK2, and phosphorylation of ATG16L1 is induced by H/R in a CSNK2-dependent manner. Phosphorylation of ATG16L1 on Ser139 has not been observed previously.…”

Protein Kinase CK2 and Angiogenesis

“…By phosphorylating [57][58][59] or interacting with Akt [60,61], CK2 can modulate the activity of several angiogenic mediators simultaneously. Furthermore, CK2 is acting upstream of ERK1/2 and p38 MAPK and might thus also modulate the MAP kinase pathway, which is initiated by VEGF and IGF-1 [62,63]. Interestingly, it was also shown than CK2 can modulate HIF-1a either directly [64,37] or by the phosphorylation of the HIF-1a interacting VHL protein [65].…”

The Protein Kinase 2 Inhibitor CX-4945 Induces Autophagy in Human Cancer Cell Lines

“…18,19 CK2 is involved in apoptosis and autophagy via regulation of signaling pathways, including the mTOR pathway. 21,22 Despite this anti-cancer and anti-EMT activity in several types of human cancers, no studies have investigated CX-4945-mediated autophagic cell death.…”