CK2 Inhibitors Enhance the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells Through Inhibition of Stat3 Activation

Abstract

CK2 interacts and phosphorylates >300 proteins, including Stat3, and is linked to a number of human cancers. Constitutively activated Stat3 has been reported in 50% of human lung cancers. Inhibition of CK2 activity can induce apoptosis and suppression of Stat3 activation in cancer cells. This study examined the effects of CK2 inhibitors on growth inhibition of lung cancer cells and the therapeutic potential on lung cancer. The CK2 inhibitor and radiation both suppressed cancer cell growth in a dose-dependent manner. Besides, the cytotoxic effect of irradiation could be augmented by CK2 inhibitors (p<0.05, two-way analysis of variance and Tukey's Honestly Significant Difference). Moreover, the growth inhibition of CK2 inhibitor and irradiation was both associated with suppression of Stat3 activation. Taken together, inhibition of CK2 activity appears to be a promising treatment strategy for non-small cell lung cancer and CK2 inhibition results in reduced Stat3 activation. Our data warrant further effort to develop CK2-targeted radiosensitizer for lung cancer treatment.

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells

“…In addition, similar to PIM1, CK2 is constitutively active, and is highly associated with tumorigenesis and radioresistance [55,56]. According to structural analysis of dual inhibitors for PIM1 and CK2, dual inhibitors tend to be usually flat-form structures and could be occupied in the ATP-binding site by lots of hydrophobic interactions between the aromatic rings of the inhibitors and the several hydrophobic residues near the binding pocket in active site [53,[57][58][59].…”

“…It is meaningful that tryptanthrin shows the possibility of functional duality since both PIM1 and CK2 are considered to be critical regulators for rendering radioresistance. Recent study has found that the inhibition of CK2 is correlated with radiosensitization via suppressing proliferative activity of Stat3 in NSCLC cells [56]. Blocking single radioresistant signaling used by a specific inhibitor might be, at least in part, insufficient for the regulation of radiosensitivity, because it could not be completely excluded the possibility that compensatory signaling response mediated by CK2 as a crosstalk pathway might be involved in radioresistance of NSCLC [60].…”

Protein Kinase CK2 Cellular Function in Normal and Disease States

“…This model is strongly supported by the fi ndings that E(spl) proteins directly interact with ASC/Atonal in biochemical and yeast two-hybrid assays [ 121 -125 ]. The observation that CK2 phosphorylates E(spl)-M8, E(spl)-M7, and E(spl)-M5 [ 126 ] has revealed the importance of posttranslational modifi cation (PTM) in the regulation of these Notch effectors, raised the prospect of nonredundancy, and begun to unravel the mechanism by which a dominant mutation in the m8 gene ( E(spl)D ) abolishes eye development.…”

“…We had identifi ed that CK2 phosphorylates M8/M5/M7 (see Fig. 2 ) at a highly conserved site in the region deleted in M8* [ 126 ]. Remarkably, in the case of M8, replacement of the CK2 phosphoacceptor (Ser 159 ) with Asp resulted in a form of the protein that mimicked the eye defects of M8* ( E(spl)D ), and both M8-S 159 D and M8* displayed equivalent interactions with Atonal that were not seen with wild-type M8 or its CK2 refractory variant M8-S 159 A [ 125 ].…”

Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors

“…CK2 phosphorylates many substrates and participates in the complex series of cellular functions such as progression of the cell cycle, apoptosis, cell differentiation and transcription processes 1 . CK2 overexpression and hyper-activation are observed in a large number of tumors 2 , including breast cancer 3 , lung 4 , prostate 5 , colon 6 , kidney 7 and hematological malignancies 8 . Recently, it was reported that the decrease in CK2 regulation plays a critical role in inflammatory 9 and infectious diseases 10 .…”