Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA306215 | ENA |
REPOSITORIES: ENA
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Project description:Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. The NF-kBsignalling pathway deregulation has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-kBwas hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-kB inhibitor. The concomitant combination of Curcumin+OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion oftheir resistant phenotype, through the inhibition of the NF-kBsignalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-KB-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells thatwere more efficiently down-regulated after OXA+Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-kBpathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastaseswas associated with response to OXA+Curcumin.In conclusion, we suggest that combination of OXA+Curcumincould be an effective treatment in CRC patients after progression to OXA-based chemotherapy being CXCL1a good candidate predictive marker to this treatment.
2016-12-07 | GSE76092 | GEO
Project description:The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kB signaling. Here we evaluated the CSCs-depleting potential of NF-kB inhibition in liver cancer achieved by IKK inhibitor curcumin and specific peptide SN50 . The effects on CSCs were assessed by analysis of Side Population (SP) and expression levels of CSC-related genes as determined by RT-qPCR, gene expression microarray, EMSA, and Western blotting. Curcumin caused anti-proliferative and pro-apoptotic responses directly related to the extent of NF-kB inhibition. In curcumin-sensitive tumor cells, the treatment led to a selective CSC depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kB inhibition by SN50 caused a general suppression of cell growth accompanied by a reduced SP fraction. In contrast, curcumin-resistant cells exhibited a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, CSC-depleting activity of curcumin was exerted by the NF-kB-mediated HDAC inhibition causing down-regulation of c-MYC and other key oncogenic targets. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitity with our HCC database indicated that HCC patients with poor prognosis and progenitor features are most likely to benefit from NF-kB inhibition. These results demonstrate that NF-kB inhibition can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis. Five human hepatoma cell lines with and without curcumin
2015-12-31 | E-GEOD-59713 | biostudies-arrayexpress
Project description:The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kB signaling. Here we evaluated the CSCs-depleting potential of NF-kB inhibition in liver cancer achieved by IKK inhibitor curcumin and specific peptide SN50 . The effects on CSCs were assessed by analysis of Side Population (SP) and expression levels of CSC-related genes as determined by RT-qPCR, gene expression microarray, EMSA, and Western blotting. Curcumin caused anti-proliferative and pro-apoptotic responses directly related to the extent of NF-kB inhibition. In curcumin-sensitive tumor cells, the treatment led to a selective CSC depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kB inhibition by SN50 caused a general suppression of cell growth accompanied by a reduced SP fraction. In contrast, curcumin-resistant cells exhibited a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, CSC-depleting activity of curcumin was exerted by the NF-kB-mediated HDAC inhibition causing down-regulation of c-MYC and other key oncogenic targets. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitity with our HCC database indicated that HCC patients with poor prognosis and progenitor features are most likely to benefit from NF-kB inhibition. These results demonstrate that NF-kB inhibition can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis.
2015-12-31 | GSE59713 | GEO
Project description:The inflammatory gene response requires activation of the protein kinase TAK1, but it is currently unknown how TAK1-derived signals coordinate transcriptional programs in the genome. We determined the genome-wide binding of the TAK1-controlled NF-?B subunit p65 in relation to active enhancers and promoters of transcribed genes by ChIP-seq experiments. Out of 35,000 active enhancer regions, 410 H3K4me1-positive enhancers show interleukin (IL)-1-induced H3K27ac and p65 binding. Inhibition of TAK1, IKK2 or depletion of p65 blocked inducible enhancer activation and gene expression. As exemplified by the CXC chemokine cluster located on chromosome 4, the TAK1-p65 pathway also regulates the recruitment kinetics of the histone acetyltransferase CBP, of NF-?B p50 and of AP-1 transcription factors to both, promoters and enhancers. This study provides a high resolution view of epigenetic changes occurring during the IL-1 response and allows the first genome-wide identification of a novel class of inducible p65 NF-?B-dependent enhancers in epithelial cells. RNA-seq of KB cells either untreated or treated with IL-1 alpha
2014-12-16 | E-GEOD-64185 | biostudies-arrayexpress
Project description:The inflammatory gene response requires activation of the protein kinase TAK1, but it is currently unknown how TAK1-derived signals coordinate transcriptional programs in the genome. We determined the genome-wide binding of the TAK1-controlled NF-κB subunit p65 in relation to active enhancers and promoters of transcribed genes by ChIP-seq experiments. Out of 35,000 active enhancer regions, 410 H3K4me1-positive enhancers show interleukin (IL)-1-induced H3K27ac and p65 binding. Inhibition of TAK1, IKK2 or depletion of p65 blocked inducible enhancer activation and gene expression. As exemplified by the CXC chemokine cluster located on chromosome 4, the TAK1-p65 pathway also regulates the recruitment kinetics of the histone acetyltransferase CBP, of NF-κB p50 and of AP-1 transcription factors to both, promoters and enhancers. This study provides a high resolution view of epigenetic changes occurring during the IL-1 response and allows the first genome-wide identification of a novel class of inducible p65 NF-κB-dependent enhancers in epithelial cells. ChIP-seq in KB cells with 5 different antibodies under different treatment conditions
2014-12-16 | E-GEOD-64223 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-kB and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-kB activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-kB activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-kB and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-kB in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
2023-04-24 | PXD038951 | Pride
Project description:The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors.
The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.
2024-05-09 | PXD037534 | JPOST Repository
Project description:First, in a model of xenografts induced with HT-29 human colon cancer cells, we demonstrated that the transcription factor NF-kB was involved in the resistance to CPT-11. Then, from one tumor treated with CPT-11 plus a NF-kB inhibitor, we established a resistant cell line to CPT-11. The aim of this study was to compare the expression of genes involved in the signaling pathway of NF-kB between the sensitive and the resistant cell lines and to identify other genes (target or not of NF-kB) which the expression was modified when the resistant phenotype was acquired.
2012-08-23 | GSE23433 | GEO
Project description:The canonical NF-kB module induces nuclear translocation of RelA heterodimers from the latent cytoplasmic complexes. RelA directs inflammatory immune responses against microbial entities. However, aberrant RelA activity also triggers destructive inflammation, including those associated with inflammatory bowel disease (IBD). What provokes this pathological RelA activity remains unclear. As such, the noncanonical NF-kB pathway activates RelB heterodimers and mediates immune organogenesis. Because NF-kB-activating pathways are interlinked, we asked if noncanonical NF-kB signaling exacerbated intestinal inflammation. Our investigation revealed recurrent engagement of the noncanonical pathway in human IBD. In a mouse model of chemical colitis, the noncanonical NF-kB signaling gene Nfkb2 aggravated inflammation by amplifying the RelA activity induced in intestinal epithelial cells. Our mechanistic studies clarified that noncanonical signaling augmented the abundance of latent RelA complexes leading to hyperactive canonical NF-kB response in the colitogenic gut. In sum, latent dimer homeostasis appears to link noncanonical NF-kB signaling to RelA-driven inflammatory pathologies.
2021-07-07 | GSE148577 | GEO
Project description:First, in a model of xenografts induced with HT-29 human colon cancer cells, we demonstrated that the transcription factor NF-kB was involved in the resistance to CPT-11. Then, from one tumor treated with CPT-11 plus a NF-kB inhibitor, we established a resistant cell line to CPT-11. The aim of this study was to compare the expression of genes involved in the signaling pathway of NF-kB between the sensitive and the resistant cell lines and to identify other genes (target or not of NF-kB) which the expression was modified when the resistant phenotype was acquired. Human colon cancer cells chemosensitive (HT-29) versus human colon cancer cells chemoresistant (RIV) in a dye-swap experiment.
2012-08-23 | E-GEOD-23433 | biostudies-arrayexpress