casein-kinase-ii and Stomach-Neoplasms

Topics: Animals; Casein Kinase II; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stomach Neoplasms; Zinc

Accumulating evidence has highlighted the importance of negative elongation factor complex member E (NELFE) in tumorigenesis. However, the relationship between NELFE and gastric cancer (GC) remains unclear. This study aimed to explore the expression pattern and specific function of NELFE in GC.. NELFE expression was evaluated by immunohistochemistry and qRT-PCR in GC tissues, respectively. Cell proliferation, migration and invasion were measured by CCK-8, colony formation, transwell assays, and nude mice model. Bioinformatics analysis was performed to search potential target genes of NELFE, and a Cignal Finder 10-Pathway Reporter Array was used to explore potential signaling pathways regulated by NELFE. Dual-luciferase reporter assays, qRT-PCR and western blotting were conducted to verify their regulatory relationship. The expression correlations among NELFE, β-catenin and CSNK2B were further explored by immunohistochemistry on consecutive resections.. NELFE was significantly overexpressed in GC tissues both in protein and mRNA level and negatively correlated with the prognosis of GC patients. Gain- and loss-of-function experiments showed that NELFE potentiated GC cell proliferation and metastasis in vitro and in vivo. CSNK2B was identified as a downstream effector of NELFE. Wnt/β-catenin signaling may mediate the regulation of CSNK2B by NELFE. In addition, NELFE, β-catenin and CSNK2B were all remarkably upregulated in tumor tissues compared with adjacent normal tissues, and their expression levels in GC were positively correlated with each other.. Our findings reveal a new NELFE-Wnt/β-catenin-CSNK2B axis to promote GC progression and provide new candidate targets against this disease.

Topics: Animals; Casein Kinase II; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Mice; Neoplasm Metastasis; Stomach Neoplasms; Transcription Factors; Wnt Signaling Pathway

Casein kinase 2 (CK2) has become a potential therapeutic target in gastric cancer; however, the underlying mechanism remains incompletely understood. TAp73, a structural homolog of the tumor suppressor p53, acts as a critical regulator of the Warburg effect. Recent study reveals that aberrant CK2 signaling is able to inhibit TAp73 function. Here we determine that TAp73 is overexpressed in AGS-1 but not in SNU-5 gastric cancer cell line as compared with normal gastric cells. In addition, we show that TAp73 expression is required for the maintenance of glucose uptake and lactate release in AGS-1 but not in SNU-5 gastric cancer cells. Importantly, the use of CX-4945, a selective inhibitor of protein kinase CK2, inhibits cell growth and invasion, and promotes cell apoptosis in AGS-1 with decreased TAp73 expression as well as downregulated glucose uptake and lactate release. Although TAp73 knockdown resulted in significant decreases in TAp73 expressions in SNU-5 cell line, no differences in glucose uptake and lactate release were observed between SNU-5 and normal gastric cells. Moreover, TAp73 gene overexpression promotes glucose uptake and lactate release and abolishes the anti-cancer effects of CX-4945 in gastric cancer cell line AGS-1. The impacts of CX-4945 on glycolysis and tumorigenesis were strongly limited in SNU-5 gastric cancer cell line. These findings suggest that CX-4945 elicits an anti-Warburg effects in gastric cancer overexpressing Tap73 and inhibits gastric tumorigenesis.

Topics: Anticarcinogenic Agents; Carcinogenesis; Casein Kinase II; Cell Line, Tumor; Down-Regulation; Humans; Naphthyridines; Phenazines; Protein Kinase Inhibitors; Stomach Neoplasms; Tumor Protein p73; Warburg Effect, Oncologic

Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC).. CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model.. Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities.. These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Casein Kinase II; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Naphthyridines; Paclitaxel; Phenazines; Progression-Free Survival; Stomach Neoplasms; Xenograft Model Antitumor Assays

RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development.

Topics: Animals; Antigens, Neoplasm; Casein Kinase II; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Histone Demethylases; Histone-Lysine N-Methyltransferase; Humans; Methylation; Mice; Phosphorylation; Protein Binding; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; SKP Cullin F-Box Protein Ligases; Stomach Neoplasms; Ubiquitination

Casein kinase 2 (CK2) is involved in multiple cellular processes. Furthermore, its overexpression in several human cancers has been associated with tumor progression. In this study, we evaluated the efficacy of the CK2 inhibitor, CX-4945, in gastric cancer cell lines and explored the potential predictive biomarkers for CX-4945 sensitivity.. The sensitivity to CX-4945 was screened in 49 gastric cancer cell lines by the MTT assay. The mRNA and protein expression of CK2 subunits (α and α') were determined using qRT-PCR and western blot. Furthermore, the activity of CK2α was measured by ELISA. Gene expression and mutations were analyzed via whole-exome and RNA sequencing.. The sensitivity to CX-4945 was determined by the inhibition rate (%) at the effective dose (10 μM) which ranged from -1% to 89% in 49 gastric cancer cell lines. CK2α', but not CK2α, mRNA expression was correlated with CX-4945 sensitivity.. In this study, CX-4945 showed modest antitumor efficacy in gastric cancer cell lines. CK2 might represent a potential therapeutic target for gastric cancer.

Topics: Casein Kinase II; Cell Line, Tumor; Humans; Molecular Targeted Therapy; Mutation; Naphthyridines; Phenazines; RNA, Messenger; Stomach Neoplasms

Pt(IV) prodrugs, with two additional coordination sites in contrast to Pt(II) drugs, have been actively studied nowadays, for they can perform well in enhancing the accumulation and retention of the corresponding Pt(II) drugs in cancer cells. Our designed Pt(II) drug, DN604, was recently found to exhibit significant anticancer activity and low toxicity, while, wogonin, a naturally O-methylated flavones, has been widely investigated for its tumor therapeutic potential. Thus, two Pt(IV)-based prodrugs were derived by addition of a wogonin unit to the axial position of DN604 and its analogue DN603 via a linker group. In vitro cytotoxicity assay indicated that the resulting compound 8 not only inherited the genotoxicity of DN604 on gastric cancer cells, but also obtained the COX inhibitory property arising from wogonin. Further studies revealed that compound 8 caused the accumulation of ROS production and decreased the mitochondrial membrane potential (ΔΨm). The CK2α kinase activity assay, ChIP and luciferase assays showed that CK2 plays an important role in the blockade of compound 8 on activated NF-κB survival pathways, which were established for sensitivity of cancer cells to platinum drugs. Similarly in vivo, in nude mice with SGC-7901/cDDP xenografts, compound 8 improved the effectiveness of DN604 via reversing tumor resistance and maintaining low toxicity. Overall, compound 8 is a promising Pt(IV) prodrug, which could be used to promote the anticancer activity of its counterpart Pt(II) species and reverse drug resistance via attenuating CK2-mediated NF-κB pathways during platinum-based chemotherapies.

Topics: Animals; Antineoplastic Agents; Casein Kinase II; Cisplatin; Drug Resistance, Neoplasm; Flavanones; HCT116 Cells; Hep G2 Cells; Human Umbilical Vein Endothelial Cells; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Organoplatinum Compounds; Prodrugs; Random Allocation; Signal Transduction; Stomach Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

CK2α has diverse effects on the tumorigenesis owing to its kinase activity, which phosphorylates various proteins involved in tumorigenesis. We, therefore, investigated the expression and role of CK2α in the phosphorylation of deleted in breast cancer 1 (DBC1) in gastric carcinomas. We used 187 gastric carcinomas and human gastric cancer cells to investigate the roles and relationship between CK2α and DBC1 in gastric carcinomas. Positive expression of CK2α and phospho-DBC1 predicted shorter overall survival and relapse-free survival by univariate analysis. Especially, CK2α expression was an independent prognostic indicator for gastric carcinoma patients. In gastric carcinoma cells, CK2α was bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2α was evidenced by co-immunoprecipitation of CK2α and DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. Inhibition of both CK2α and DBC1 decreased proliferation and invasive activity of cancer cells. Decreased migration and invasive activity was associated with a downregulation of MMP2, MMP9 and the epithelial-mesenchymal transition. A mutation at the phosphorylation site of DBC1 also downregulated the signals related with the epithelial-mesenchymal transition. Our study demonstrated that CK2α is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. In addition, the blocking of CK2α and DBC1 inhibited the proliferation and invasive potential of gastric cancer cells. Therefore, our study suggests that CK2α-DBC1 pathway might be a new therapeutic target for the treatment of gastric carcinoma.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Casein Kinase II; Cell Movement; Cell Proliferation; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Phosphorylation; Prognosis; Protein Processing, Post-Translational; Stomach Neoplasms

The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5(WT) in PDCD5(-/-) MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions.

Topics: Animals; Apoptosis Regulatory Proteins; Casein Kinase II; Cell Line, Tumor; Chromatin Immunoprecipitation; DNA Damage; Fibroblasts; Gene Expression Profiling; HCT116 Cells; Histone Deacetylases; Humans; Immunoprecipitation; In Situ Nick-End Labeling; Karyopherins; Mass Spectrometry; Mice; Mice, Knockout; Neoplasm Proteins; Neoplasm Transplantation; Phosphorylation; Prognosis; Proteasome Endopeptidase Complex; Real-Time Polymerase Chain Reaction; Stomach Neoplasms; Tumor Suppressor Protein p53

Gastric cancer as one of the most common cancers worldwide has various genetic and environmental risk factors including Helicobacter pylori (H.pylori) infection. Recently, loss of a tumor suppressor gene named promyelocytic leukemia (PML) has been identified in gastric cancer. However, no mutation has been found in this gene in gastric cancer samples. Cag A H.pylori protein has been shown to exert post transcriptional regulation of some tumor suppressor genes. In order to assess such a mechanism for PML degradation, we performed in silico analyses to establish any interaction between PML and Cag A proteins. In silico interaction and docking studies showed that these two proteins may have stable interactions. In addition, we showed that imatinib kinase inhibitor can restore PML function by inhibition of casein kinase 2.

Topics: Antigens, Bacterial; Bacterial Proteins; Casein Kinase II; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Imatinib Mesylate; Molecular Docking Simulation; Nuclear Proteins; Promyelocytic Leukemia Protein; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors; RNA Processing, Post-Transcriptional; Stomach Neoplasms; Transcription Factors; Tumor Suppressor Proteins

The development of cancer resistance to chemotherapy is the major obstacle to cancer therapy. Here, we identified that the phosphorylation of apoptosis repressor with caspase recruitment domain (ARC) at threonine 149 was essential to inhibit doxorubicin (DOX) induced apoptosis and mitochondrial fission in cancer cells. Our further study showed that casein kinase II (CK2) inhibitors could decrease the phosphorylation levels of ARC and make cancer cells sensitive to undergoing apoptosis. Furthermore, CK2α and CK2α', catalytic subunits of CK2, were observed to translocate into nuclear in cancer cells with the treatment of DOX. Finally, the synergistically therapeutic effect by combining DOX and CK2 inhibitor was confirmed in tumor xenograft model. Taken together, our results revealed that CK2-mediated phosphorylation of ARC contributed to chemotherapy resistance by inhibiting DOX induced apoptosis and combining DOX with CK2 inhibitor could induce apoptosis of cancer cells synergistically by down-regulating the phosphorylation of ARC. Therefore, development of new therapeutic strategies based on ARC and CK2, is promising for overcoming cancer resistance to chemotherapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Casein Kinase II; Caspases; Cell Line, Tumor; Cell Nucleus; Cell Survival; Cytoskeletal Proteins; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Neoplasm Transplantation; Nerve Tissue Proteins; Phosphorylation; Protein Structure, Tertiary; Stomach Neoplasms

Gastric carcinoma is one of the most common malignancies in the world, yet little is known about the molecular process of its development and progression. The aims of this study are to correlate the expression of nuclear protein kinase CK2 beta subunit (CK2beta) with clinicopathologic parameters and patient survival.. Expression levels of nuclear CK2beta were analyzed in 104 gastric tissues from patients with gastric carcinoma by immunohistochemistry. A paired t test was used to analyze the differences in nuclear CK2beta expression between tumor and nontumor tissues in the same patient. A two-tailed chi (2) test was performed to determine the significance of the difference between nuclear CK2beta expression and clinicopathologic parameters. All time-to-event endpoints according to various clinicopathologic parameters were plotted by Kaplan-Meier method, and significance was then determined by univariate log-rank test. Cox proportional-hazards model was used for multivariate analysis to determine the independence of prognostic impact of nuclear CK2beta expression.. Overexpression of nuclear CK2beta was significantly correlated with depth of invasion (P = 0.042). Patients with high expression levels of nuclear CK2beta had a significantly poorer overall survival rate compared with patients with low expression levels of nuclear CK2beta (P = 0.0006). On multivariate Cox regression analysis, overexpression of nuclear CK2beta and stage were proven to be independent prognostic markers for gastric carcinoma (P = 0.0036 and 0.0005, respectively).. Overexpression of nuclear CK2beta can be a useful marker for predicting the outcome of patients with gastric carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma; Casein Kinase II; Cohort Studies; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Stomach Neoplasms; Survival Analysis

The purpose of this study was to investigate the anticancer effect of aloe-emodin, an anthraquinone compound present in the leaves of Aloe vera, on two distinct human gastric carcinoma cell lines, AGS and NCI-N87. We demonstrate that aloe-emodin induced cell death in a dose- and time-dependent manner. Noteworthy is that the AGS cells were generally more sensitive than the NCI-N87 cells. Aloe-emodin caused the release of apoptosis-inducing factor and cytochrome c from mitochondria, followed by the activation of caspase-3, leading to nuclear shrinkage and apoptosis. In addition, exposure to aloe-emodin suppressed the casein kinase II activity in a time-dependent manner and was accompanied by a reduced phosphorylation of Bid, a downstream substrate of casein kinase II and a pro-apoptotic molecule. These preclinical studies suggest that aloe-emodin represents a suitable and novel chemotherapeutic drug candidate for the treatment of human gastric carcinoma.

Topics: Anthraquinones; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Inducing Factor; BH3 Interacting Domain Death Agonist Protein; Carcinoma; Casein Kinase II; Cell Line, Tumor; Cytochromes c; Dose-Response Relationship, Drug; Humans; Phosphorylation; Stomach Neoplasms; Time Factors