Association of protein kinase CK2 inhibition with cellular radiosensitivity of non-small cell lung cancer

Qianwen Li,Fangzheng Zhou,Li Liu,Xiaoshu Zhou,Rui Meng,Ke Li,Jinrong Xiong,Yu Zhou,Sheng Zhang,Tianyang Yang,Zhenyu Li,Gang Wu

doi:10.1038/s41598-017-16012-1

Abstract

Protein kinase CK2 is a highly conserved protein Ser/Thr protein kinase and plays important roles in cell proliferation, protein translation and cell survival. This study investigated the possibility of using CK2 inhibition as a new approach for increasing the efficacy of radiotherapy in non-small cell lung cancer (NSCLC) and its underlying mechanisms. Kinase inhibition of CK2 was attempted either by using the specific CK2 inhibitor, Quinalizarin or by applying siRNA interference technology to silence the expression of the catalytic subunit of CK2 in A549 and H460 cells. The results showed that CK2α knockdown or Quinalizarin significantly enhanced the radiosensitivity of various NSCLC cells. The notable findings we observed after exposure to both CK2 inhibition and ionizing radiation (IR) were a prolonged delay in radiation-induced DNA double-strand breaks (DSB) repair, robust G2/M checkpoint arrest and increased apoptosis. In vivo studies further demonstrated that compared with each treatment alone, CK2 inhibition combined with IR reduced tumor growth in the H460 cell xenograft model. In conclusion, CK2 is a promising target for the enhancement of radiosensitivity in NSCLC.

Highlights

Lung cancer is the leading cause of cancer deaths worldwide, affecting approximately 1.6 million people worldwide each year[1]
We observed a significant increase in the cell population in G2/M phase (19.01 ± 0.46% in A549 and 35.94 ± 1.21% in H460) compared with that in Quinalizarin group (9.46 ± 0.76% in A549 and 12.82 ± 0.48% in H460) or ionizing radiation (IR) group (9.79 ± 0.76% in A549 and 19.50 ± 0.44% in H460) (Fig. 5)
In vivo studies were conducted on the H460 tumor xenograft mice model. We found that both Quinalizarin and IR suppressed H460 tumor growth, and the inhibitory effect was greater in the combination group (Fig. 8A)

Summary

Introduction

Lung cancer is the leading cause of cancer deaths worldwide, affecting approximately 1.6 million people worldwide each year[1]. There are more than 300 CK2 substrates, which played vital roles in cell proliferation, apoptosis and DNA damage repair regulation processes[8,9,10,11]. It is noteworthy that some of these CK2 substrates are key molecules involved in the major cellular processes after radiation. These include XRCC4 and MDC1, which played key roles in the DNA double-stand breaks repair process and are phosphorylated and regulated by CK212,13. We investigated the radiosensitizing effect of the down regulation of CK2 in various lung cancer cell lines and tried to identify the underlying mechanisms using in vivo and in vitro experiments

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Results

Conclusion