NRF2 signalling associated with radioresistance in colorectal cancer models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA560938 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10004274_1.fastq.gz | Fastqsanger.gz | |||
| SRR10004274_2.fastq.gz | Fastqsanger.gz | |||
| SRR10004275_1.fastq.gz | Fastqsanger.gz | |||
| SRR10004275_2.fastq.gz | Fastqsanger.gz | |||
| SRR10004276_1.fastq.gz | Fastqsanger.gz |
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Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2. Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.
2015-10-31 | E-GEOD-71695 | biostudies-arrayexpress
Project description:Oxidative stress reduces haematopoietic stem cell (HSC) function with age, and increased reactive oxygen species (ROS) levels promote DNA damage, cell senescence, and haematopoietic dysfunction. DDO1002, an effective Keap1–Nrf2 inhibitor, may regulate antioxidant gene expression, however, its ability to alleviate impaired haematopoiesis following total body irradiation (TBI) or ageing remains unclear. Through both cellular and mouse models, we showed that DDO1002 upregulated Nrf2, activated the Nrf2-mediated antioxidant response element (ARE) signalling pathway, reduced intracellular ROS levels and delayed cellular senescence. Moreover, DDO1002 reduced DNA damage and HSC apoptosis, thereby increasing the number of HSCs, lymphoid-primed MPP4 cells, and B cells in peripheral blood. Therefore, DDO1002 alleviates TBI-induced haematopoietic injury. Similarly, DDO1002 treatment activated the expression of Nrf2 and Nrf2-mediated ARE signalling pathways in the bone marrow cells of naturally ageing mice. B and T cell proportions in the spleen were increased, as was the colony-forming ability of bone marrow cells. Single-cell sequencing analysis revealed that DDO1002 treatment attenuated intracellular inflammatory signalling pathways and reduced the ROS pathway in aged HSCs, suggesting an ability to restore aged-HSC viability. Thus, DDO1002 effectively activated Nrf2 to delay cell senescence and improved impaired haematopoiesis via the Nrf2–ARE pathway, showing potential for treating age-related haematopoietic disorders.
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Project description:We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signalling cascade plays an essential role in TNFα-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of CRC, which may provide potential targets for the treatment of colorectal cancer.
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Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.
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Project description:WGS and RNA-seq data for Nrf2 study
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Project description:Understanding the structure and interplay of cellular signalling pathways is one of the great challenges in molecular biology. Boolean Networks can infer signalling networks from observations of protein activation. In situations where it is difficult to assess protein activation directly, Nested Effect Models are an alternative. They derive the network structure indirectly from downstream effects of pathway perturbations. To date, Nested Effect Models cannot resolve signalling details like the formation of signalling complexes or the activation of proteins by multiple alternative input signals. Here we introduce Boolean Nested Effect Models (B-NEM). B-NEMs combine the use of downstream effects with the higher resolution of signalling pathway structures in Boolean Networks. We show that B-NEMs accurately reconstruct signal flows in simulated data. Using B-NEM we then resolve BCR signalling via PI3K and TAK1 kinases in BL2 lymphoma cell lines. 84 BL2 cell-line samples were hybridized to HGU133+2 Affymetrix GeneChips.
2015-12-10 | E-GEOD-68761 | biostudies-arrayexpress
Project description:Background: Research using in vitro canine mammary carcinoma cell lines and studies involving naturally occurring canine mammary tumours are not only fundamental models used to advance the understanding of cancer in veterinary patients but are also regarded as excellent translational models for human breast cancer. In human medicine, following disease classification and staging breast cancer is typically treated with multimodal therapies including radiotherapy. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Comparative canine and human studies investigating the molecular mechanisms of radioresistance may lead to the development of effective cancer treatments that benefit both species. Methods: Human (MDA-MB-231, MCF-7 and ZR-751) and canine (REM-134) radioresistant cell lines were established by exposing parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Intrinsic differences between parental and radioresistant cells were investigated by whole-transcriptome gene expression analysis. Gene enrichment and pathway-focused analyses identified signalling networks differentially activated in radioresistant cells. Results: Colony formation assays identified a range of intrinsic radiosensitivities in the human and canine parental cell lines with the REM-134 cell line showing significantly greater radioresistance compared to the human cell lines. Colony formation and proliferation assays confirmed radioresistance in all developed radioresistant cell lines. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Gene analysis identified that following the acquisition of radioresistance in MCF-7 and ZR-751 cell lines the cell lines changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. MDA-MB-231 and MDA-MB-231 RR cell lines both classified as basal, whereas the REM-134 and REM-134 RR cell lines with enriched for HER2 overexpression. Whole-transcriptome gene expression analysis identified down-regulation of ER signalling genes and up-regulation of genes associated with PI3K, MAPK and WNT pathway activity in radioresistant cell lines derived from ER+ cells; this was confirmed by western blot, which showed increased p-AKT and p-ERK expression following radiation. Conclusions: To our knowledge, our study is the first to develop a canine radioresistant cell line and provide a comparative genetic and phenotypic analysis of the mechanisms of acquired radioresistance between canine and human cell lines. The cellular process that occur with the development of acquired radioresistance are similar between the human and canine cell lines; this suggests that not only is the canine model an appropriate model to study human disease but that treatment strategies used in human medicine may also be applicable to veterinary patients.
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Project description:Purpose: Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ~20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well-studied. Experimental Design: We generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed using Western blotting, immunohistochemistry, RNA sequencing (RNA-seq), and subjected to fractionated radiation therapy to investigate the role of the KEAP1/NRF2 pathway in radioresistance and modulation of the tumor immune microenvironment. Results: BAP exposure accelerated primary tumor formation within one month, with histological analysis confirming invasive squamous cell carcinoma, validated by cytokeratin and differentiation marker expression. Primary cell lines derived from Keap1-haploinsufficient tumors exhibited upregulation of NRF2 target genes and a radioresistant phenotype, which was reversed post-Nrf2 knockdown in vitro. Bulk RNA-seq revealed that Keap1 haploinsufficiency correlated with NRF2 pathway activation, increased myeloid infiltration, and enhanced angiogenic signatures. In vivo, Keap1 haploinsufficiency promoted accelerated tumor growth and decreased survival. Finally, using fractionated radiotherapy, we showed that Keap1 haploinsufficient primary tumors were significantly more radioresistant than Keap1-proficient tumors, regardless of BAP exposure. Conclusion: These data demonstrate that Keap1 haploinsufficiency in HNSCC is linked to unfavorable tumor immune microenvironment, aggressive growth, and a radioresistant phenotype.
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Project description:chromatin Remodeling in Patient-Derived Colorectal Cancer Models
| PRJNA764740 | ENA