cx-4945 and Carcinoma--Non-Small-Cell-Lung

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.. 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.. 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.

Topics: Anthraquinones; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Casein Kinase II; Cytokines; Endothelial Cells; Endothelium, Vascular; Humans; Lung Neoplasms; Naphthyridines; Phenazines; Protein Kinase Inhibitors

Protein kinase CK2 is a ubiquitously expressed kinase in eukaryotes, which is known to phosphorylate many protein substrates. Because CK2 is involved in the regulation of various signaling pathways, we wondered whether CK2 participated in the regulation of ionizing radiation (IR) induced biological process. In this study, we investigated the effect of IR on the subcellular localization and kinase activity in human non-small cell lung cancer (NSCLC) cells. Immunofluorescent results showed that CK2 subunits shuttle into the nucleus mostly beginning 1 h after IR and lasting more than 6 h. We also conducted in vitro kinase assay and observed an increase in CK2 kinase activity at 6 h after IR. Furthermore, an increase in S phase was observed at 6 h after IR. Colony formation assay results demonstrated that CK2 inhibitor CX-4945 significantly enhanced the effect of irradiation in NSCLC cells. These results indicated that CK2 may be implicated in the regulation of IR-induced biological process.

Topics: Carcinoma, Non-Small-Cell Lung; Casein Kinase II; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Cell Survival; Cytoplasm; Cytosol; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genotype; Humans; Lung Neoplasms; Naphthyridines; Phenazines; Phosphorylation; Radiation, Ionizing; Signal Transduction

The response to chemotherapeutic drugs in non-small cell lung cancer (NSCLC) is unsatisfactory, leading to poor outcomes. This study the aimed to investigates anticancer effects of CX-4945, a potent casein kinase II (CK2) inhibitor, in chemorefractory NSCLC cells.. Cell proliferation and apoptosis assay were carried-out by annexin V-FITC and FACScan after drug treatment with paclitaxel, cisplatin and CX-4945. AKT/mTOR and CK2α signals were measured by western blotting. Treatment was carried-out using siRNA to inhibit CK2α.. Paclitaxel, and cisplatin effectively inhibited cell proliferation and induced apoptosis in A549 cells, while not in H1299, Calu-1 and H358 cells. In these chemorefractory cell lines, AKT signalling was maintained despite drug treatment. However, CX-4945 suppressed cell growth, with cell-cycle arrest at G2/M phase and induced apoptosis with an increase of cleaved caspase-3 and PARP1 in a dose-dependent manner. Accordingly, AKT and its downstream signals such as mTOR and p70S6K were down-regulated by CX-4945. Transfection of CK2α siRNA had similar effects to CX-4945 treatment on cell proliferation and apoptosis.. CX-4945 shows a promising anticancer action through down-regulation of AKT/mTOR signals, suggesting its possible application for treatment of chemorefractory lung cancer.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Casein Kinase II; Cell Cycle Checkpoints; Cell Line, Tumor; Cisplatin; Down-Regulation; Humans; Lung Neoplasms; Naphthyridines; Paclitaxel; Phenazines; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases