Involvement of endothelial CK2 in the radiation induced perivascular resistant niche (PVRN) and the induction of radioresistance for non-small cell lung cancer (NSCLC) cells

Abstract

Background Tumor microenvironment (TME) plays a vital role in determining the outcomes of radiotherapy. As an important component of TME, vascular endothelial cells are involved in the perivascular resistance niche (PVRN), which is formed by inflammation or cytokine production induced by ionizing radiation (IR). Protein kinase CK2 is a constitutively active serine/threonine kinase which plays a vital role in cell proliferation and inflammation. In this study, we investigated the potential role of CK2 in PVRN after IR exposure. Result Specific CK2 inhibitors, Quinalizarin and CX-4945, were employed to effectively suppressed the kinase activity of CK2 in human umbilical vein endothelial cells (HUVECs) without affecting their viability. Results showing that conditioned medium from IR-exposed HUVECs increased cell viability of A549 and H460 cells, and the pretreatment of CK2 inhibitors slowed down such increment. The secretion of IL-8 and IL-6 in HUVECs was induced after exposure with IR, but significantly inhibited by the addition of CK2 inhibitors. Furthermore, IR exposure elevated the nuclear phosphorylated factor-κB (NF-κB) p65 expression in HUVECs, which was a master factor regulating cytokine production. But when pretreated with CK2 inhibitors, such elevation was significantly suppressed. Conclusion This study indicated that protein kinase CK2 is involved in the key process of the IR induced perivascular resistant niche, namely cytokine production, by endothelial cells, which finally led to radioresistance of non-small cell lung cancer cells. Thus, the inhibition of CK2 may be a promising way to improve the outcomes of radiation in non-small cell lung cancer cells.

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex

“…The human EC line EA.hy926 was pretreated for 30 min with 10 μM CK2 inhibitor TBB (white bars) or DMSO (black bars) as solvent control, followed by 24 h control (CTRL), TNF-α or poly I:C stimulation ( Figures 2A,B ). The experimental setup was validated by mRNA expression analysis of the proinflammatory marker IL-8 (for TNF-α) or CXCL10 (for poly I:C) that have been described to be partially regulated via CK2 signaling, respectively ( Du et al, 2015 ; Li et al, 2019 ). IL-8 and CXCL10 mRNA were significantly upregulated in TNF-α ( Figure 2A , left panel) or poly I:C ( Figure 2A , right panel) treated EA.hy926 in DMSO pre-stimulated cells.…”

Role of protein kinase CK2 in antitumor drug resistance

“…In the framework of this review, it could be worth to mention that CK2 is also implicated in key processes which lead to radio-resistance: inhibition of CK2 has been found to reduce the secretion of IL-8 and IL-6 by endothelial cells after ionizing radiation (IR), and proposed as a strategy to improve the IR outcomes in non-small cell lung cancer cells [124, 129].…”

Construction of Radiation Surviving/Resistant Lung Cancer Cell Lines with Equidifferent Gradient Dose Irradiation

“…31 There are also researches report that tumor microenvironment (TME) plays a vital role in determining the responses of radiotherapy. 32 Lee etc. found that TGF-β and hypoxia/reoxygenation promote radioresistance of lung cancer cells and tumor progression through ROS-mediated activation of Nrf2 and EGFR.…”