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MicroRNA-499 serves as a sensitizer for lung cancer cells to radiotherapy by inhibition of CK2α-mediated phosphorylation of p65.

ABSTRACT: The present study aimed to define the tumor-suppressive role of microRNA-499 (miR-499) in lung cancer cells and its underlying mechanism. First, qRT-PCR analysis revealed poor expression of miR-499 in clinical samples and cell lines of lung cancer. Next, we performed loss- and gain-of-function experiments for the expression of miR-499 in lung cancer cells exposed to irradiation (IR) to determine the effect of miR-499 expression on cell viability and apoptosis as well as tumor growth. Results showed that overexpression of miR-499 inhibited cell viability, enhanced the radiosensitivity of lung cancer cells, and promoted cell apoptosis under IR. Furthermore, CK2α was verified to be a target of miR-499, and miR-499 was identified to repress p65 phosphorylation by downregulating CK2α expression, which ultimately diminished the survival rate of lung cancer cells under IR. Collectively, the key findings of the study illustrate the tumor-inhibiting function of miR-499 and confirmed that miR-499-mediated CK2α inhibition and altered p65 phosphorylation enhances the sensitivity of lung cancer cells to IR.

SUBMITTER: Ma YS

PROVIDER: S-EPMC8099482 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inhibition of CK2α down-regulates Notch1 signalling in lung cancer cells.

Project description:Protein kinase CK2 is frequently elevated in a variety of human cancers. The Notch1 signalling pathway has been implicated in stem cell maintenance and its aberrant activation has been shown in several types of cancer including lung cancer. Here, we show, for the first time, that CK2α is a positive regulator of Notch1 signalling in lung cancer cell lines A549 and H1299. We found that Notch1 protein level was reduced after CK2α silencing. Down-regulation of Notch1 transcriptional activity was demonstrated after the silencing of CK2α in lung cancer cells. Furthermore, small-molecule CK2α inhibitor CX-4945 led to a dose-dependent inhibition of Notch1 transcriptional activity. Conversely, forced overexpression of CK2α resulted in an increase in Notch1 transcriptional activity. Finally, the inhibition of CK2α led to a reduced proportion of stem-like CD44 + /CD24- cell population. Thus, we report that the inhibition of CK2α down-regulates Notch1 signalling and subsequently reduces a cancer stem-like cell population in human lung cancer cells. Our data suggest that CK2α inhibitors may be beneficial to the lung cancer patients with activated Notch1 signalling.

| S-EPMC3729857 | biostudies-literature

Restoring microRNA-499-5p Protects Sepsis-Induced Lung Injury Mice Via Targeting Sox6.

Project description:BackgroundMicroRNAs (miRs) are known to participate in sepsis; hence, we aim to discuss the protective effect of miR-499-5p targeting sex-determining region Y-related high-mobility-group box 6 (Sox6) on sepsis-induced lung injury in mice.MethodsThe sepsis-induced lung injury model was established by cecal ligation and puncture. The wet/dry weight (W/D) ratio, miR-499-5p, Sox6, Caspase-3 and Caspase-9 expression in lung tissues of mice were tested. Lung injury score, collagen fibers and the degree of pulmonary fibrosis in lung tissues were determined. Further, the cell apoptosis in lung tissues was measured. The inflammatory factors contents and oxidative stress indices in bronchoalveolar lavage fluid (BALF) and lung tissues were detected via loss- and gain-of-function assays. The targeting relation between miR-499-5p and Sox6 was verified.ResultsW/D ratio and Sox6 were increased while miR-499-5p was decreased in lung tissues of sepsis-induced lung injury mice. Restored miR-499-5p or depleted Sox6 alleviated lung tissues pathology, reduced lung injury score, collagen fibers, the degree of pulmonary fibrosis, TUNEL positive cells, Caspase-3 and Caspase-9 protein expression and inflammatory factors contents in BALF and lung tissues as well as oxidative stress response in lung tissues of sepsis-induced lung injury mice. miR-499-5p targeted Sox6.ConclusionHigh expression of miR-499-5p can attenuate cell apoptosis in lung tissues and inhibit inflammation of sepsis-induced lung injury mice via depleting Sox6, and it is a potential candidate marker and therapeutic target for sepsis-induced lung injury.

| S-EPMC8140057 | biostudies-literature

Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS.

Project description:Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-κB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio-sensitization by melatonin may have clinical benefits in thyroid cancer.

| S-EPMC5854931 | biostudies-literature

MicroRNA-499 rs3746444 polymorphism in Egyptian children with biliary atresia.

Project description:Aim of the studyWe aimed to evaluate the association of microRNA-499 rs3746444 polymorphism and biliary atresia (BA) risk and its correlation with clinic-pathologic features of BA.Material and methodsThis study was performed on 300 Egyptian children (100 BA cases, 100 cases with cholestatic liver diseases other than BA and 100 healthy controls). Routine laboratory investigations, clinical examination and abdominal ultrasound were done. All infants were genotyped for miR-499 single nucleotide polymorphisms (SNPs) (rs3746444 A>G) by real-time polymerase chain reaction (PCR) fluorescence detection on a Rotor Gene Real Time PCR System (QIAGEN, GmbH) using fluorescent labeled probes.ResultsThe AG genotype was the most prevalent genotype of miR-499 rs3746444 among the studied groups. A significantly higher frequency of the rs3746444 G allele was found in the BA cases than the other groups (odds ratio = 1.62). This polymorphism was also correlated with the degree of fibrosis in BA cases (p < 0.05). The miR-499 rs3746444 polymorphism (GG genotype) was significantly associated with severe form of BA and bad prognosis after the Kasai operation (p < 0.05). miR-499 rs3746444 polymorphism had no effect on the clinic-pathological features or the liver function status in the non-BA group.ConclusionsThere is an association between the miR-499 SNP genotypes and the occurrence of BA. The variant allele G is the predominant allele in the BA group and is associated with severe liver inflammation and bad prognosis after the Kasai operation.

| S-EPMC7592094 | biostudies-literature

Specific inhibition of CK2α from an anchor outside the active site.

Project description:The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a Kd of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α via a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.

| S-EPMC5355960 | biostudies-literature

Daam2 phosphorylation by CK2α negatively regulates Wnt activity during white matter development and injury.

Project description:Wnt signaling plays an essential role in developmental and regenerative myelination in the central nervous system. The Wnt signaling pathway is composed of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte (OL) development remains unclear. Here, we show CK2α, a Wnt/β-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt activity during OL development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of OL development, accelerating early differentiation followed by decelerating maturation and myelination. Application toward white matter injury revealed CK2α-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a unique regulatory node in the Wnt pathway that regulates OL development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration.

| S-EPMC10469030 | biostudies-literature

MTSS1 Suppresses NF-kB Activity in Lung Adenocarcinoma through Repression of RelA/p65 Phosphorylation

Project description:Metastasis suppressor 1 (MTSS1) is a 755 amino acid protein found in the cell cytoplasm which binds to actin and promotes cytoskeleton organization and is a known suppressor of lung adenocarcinoma metastasis This study demonstrated that preservation of MTSS1 protein expression in lung adenocarcinoma was associated with a 20% 5-year survival advantage in patients. Furthermore, overexpression of MTSS1 was found to reduce metastasis and disease progression in an in-vivo orthotopic lung adenocarcinoma mouse model. Nuclear factor kappa B (NF-kB), an important nuclear transcription factor, has been shown to be constitutively active in lung adenocarcinoma and strongly associated with the development of metastasis. The NF-kB RelA/p65 subunit is involved in NF-kB heterodimer formation and subsequent nuclear translocation leading to activation of NF-kB responsive gene transcription. Phosphorylation and acetylation of p65 are critical post-translational modifications required for NF-kB activation. In this study, we demonstrate that MTSS1 expression leads to decreased NF-κB mediated gene transcription through inhibition of p65 phosphorylation. These findings uncover a novel mechanism through which MTSS1 may regulate lung adenocarcinoma metastasis by impairment of NF-κB regulated gene transcription.

2024-07-07 | GSE179644 | GEO

Thr435 phosphorylation regulates RelA (p65) NF-kappaB subunit transactivation.

Project description:Phosphorylation of the RelA (p65) NF-kappaB (nuclear factor kappaB) subunit has been previously shown to modulate its ability to induce or repress transcription. In the present study we have investigated the consequences of Thr435 phosphorylation within the C-terminal transactivation domain of RelA. We confirm that Thr435 is phosphorylated in cells and is induced by TNFalpha (tumour necrosis factor alpha) treatment. Mutational analysis of this site revealed gene-specific effects on transcription, with a T435D phosphomimetic mutant significantly enhancing Cxcl2 (CXC chemokine ligand 2) mRNA levels in reconstituted Rela-/- mouse embryonic fibroblasts. Chromatin immunoprecipitation analysis revealed that this mutation results in enhanced levels of histone acetylation associated with decreased recruitment of HDAC1 (histone deacetylase 1). Moreover, mutation of this site disrupted RelA interaction with HDAC1 in vitro. Thr435 phosphorylation of promoter-bound RelA was also detected at NF-kappaB target genes following TNFalpha treatment in wild-type mouse embryonic fibroblasts. Phosphorylation at this site therefore provides an additional mechanism through which the specificity of NF-kappaB transcriptional activity can be modulated in cells.

| S-EPMC2829238 | biostudies-literature

Fangchinoline attenuates cardiac dysfunction in rats with endotoxemia via the inhibition of ERK1/2 and NF-κB p65 phosphorylation.

Project description:BackgroundCardiac dysfunction is a complication commonly encountered by patients with endotoxemia. Fangchinoline (Fan) is a natural bisbenzylisoquinoline alkaloid. This study aimed to investigate the cardioprotective effect of Fan against lipopolysaccharide (LPS)-induced acute cardiac dysfunction.MethodsRats were administered with Baicalin (100 mg/kg) and Fan (30 or 60 mg/kg) via intraperitoneal injection (i.p.) for 3 days, followed by LPS treatment (10 mg/kg, i.p.). The rats were randomly grouped (n=10): the control group, the LPS group, the LPS + Baicalin group, the LPS + Fan groups. Echocardiography and hematoxylin and eosin (HE) staining were performed to detect cardiac dysfunction. Cardiac function were also determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), ELISA, and western blot, respectively. The protective mechanisms of Fan were analyzed by western blot and qRT-PCR.ResultsLPS induced the depression of cardiac function, myocardial inflammation, and apoptosis. These changes were associated with decreased GRP78 and GADD34, increased C/EBP-homologous protein (CHOP) and cleaved caspase-12. Fan significantly reduced the release of inflammatory cytokines such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-18, and IL-6. Furthermore, Fan treatment increased superoxide dismutase (SOD) and decreased malondialdehyde (MDA. Notably, Fan inhibited myocardial apoptosis following ER stress in the LPS-induced rat model and stimulated phosphorylation activation of ERK1/2 and NF-κB p65 proteins.ConclusionsFan deficiency alleviated LPS-induced endotoxemia in rats. Therefore, Fan may be a new therapeutic approach for the treatment of cardiac dysfunction.

| S-EPMC7576032 | biostudies-literature

Daam2 phosphorylation by CK2α negatively regulates Wnt activity during white matter development and injury

Project description:Wnt signaling plays an essential role in developmental and regenerative myelination in the CNS. The Wnt signaling pathway is comprised of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte development remains unclear. Here we show CK2α, a Wnt/β-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt-activity during oligodendrocyte development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development, accelerating early differentiation followed by decelerating maturation and myelination. Application towards white matter injury revealed CK2α-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a novel regulatory node in the Wnt pathway that regulates oligodendrocyte development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration.

2023-07-13 | GSE236976 | GEO

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