Involvement of Reactive Oxygen Species in Apoptosis Induced by Pharmacological Inhibition of Protein Kinase CK2

Abstract

It has been reported that inhibition of protein kinase CK2 (CK2) with antisense oligodeoxynucleotides (ODN) is a potent inducer of apoptosis in cancer cells but not in normal cells. In this regard, the apoptotic-inducing effect is attributed to the catalytic activity of the enzyme, which phosphorylates proapoptotic proteins to inhibit their functions. In this study we investigate the role of intracellular redox status in the proapoptotic activity of CK2 inhibition in human leukemia Cem cells. We provide evidence that inhibition ofCK2 activity induces apoptotic cell death as evident by activation of caspase 3, DNA fragmentation, and phosphatidylserine externalization. Inhibition of CK2 resulted in a significant increase in intracellular hydrogen peroxide production, which we show as a critical mediator of apoptosis. To that end, apoptotic hallmarks, like DNA fragmentation and phosphatidylserine externalization, were blocked with the specific hydrogen peroxide scavenger catalase. We also show that inhibition of CK2 reduces cytosolic intracellular superoxide, a precursor of hydrogen peroxide. In summary, decreasing CK2 activity increases intracellular hydrogen peroxide, creating an intracellular environment conducive for death execution. Taken together, these data provide information on novel pathways involved in CK2 biology with implications for effective tools against drug-resistant tumors.

Knockdown of CSNK2β suppresses MDA-MB231 cells growth, induces apoptosis, inhibits migration and invasion

“…On the basis of these observations, we next evaluated the status of ROS inside the MDA-MB-231 cells since controlled production of ROS is beneficial for proliferation and viability of cancer cells but a disproportional increase of ROS can induce cell cycle arrest and at its peak can induce apoptosis of cancer cells 28,29 . In our study we found that knockdown of CSNK2β markedly induced ROS production which seems to be consistent with earlier that use of a pharmacological inhibitor which blocks catalytic activity of CK2 induced apoptosis in leukemic cell lines via up regulation of intracellular H2O2 30 . Moreover we found the G2M cell cycle arrest of MDA-MB-231 cells following knockdown of CSNK2β and in some studies it has been shown that ROS accumulation is at its peak in the G2M phase of cell cycle 31 .…”

Protein Kinase CK2 Inhibition Induces Cell Death via Early Impact on Mitochondrial Function

“…Subsequently, similar results were observed in the human leukemia Cem cell line treated with TBB. Compared with prostate cancer cell lines employed in the present work, leukemia Cem cells are significantly more sensitive to inhibition of CK2 such that in the presence of 50 mM TBB less than 40% cell survival was observed at 24 h post-treatment, and accordingly under these experimental conditions the production of ROS was shown to occur at 3 h [Hanif et al, 2009]. In these experiments, treatment of cells with the H 2 O 2 scavenger catalase for 1 h prior to treatment with TBB resulted in a 50% reduction in the production of H 2 O 2 confirming the nature of the ROS produced on inhibition of CK2 in Cem cells.…”

Emergence of protein kinase CK2 as a key target in cancer therapy

“…It now appears that CK2 may exert a broad impact on the apoptotic machinery by influencing the activity of diverse molecules and pathways involved in the regulation of apoptosis. A few of the examples are the PI3K/Akt pathway [29,30], survivin and other inhibitors of apoptosis proteins (IAPs) [31,32], caspases [33,34], proteins in the Bcl2 pathway, and reactive oxygen species pathways [35-39]. These various observations point to the global impact of CK2 on apoptotic activity in the cell, and further highlight the significance of this function of CK2 in cancer cell biology as discussed subsequently.…”