ArticleCell death & disease2014
c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- c-Rel drives pancreatic cancer metastasis through fibronectin-integrin signaling-induced isolation stress resistance and EMT.Molecular cancer · 2025Article
- O-GlcNAcylation: Sagacious Orchestrator of Bone-, Joint-, and Spine-Related Diseases.Journal of proteome research · 2025Review
- ELF3 plays an important role in defining TRAIL sensitivity in breast cancer by modulating the expression of decoy receptor 2 (DCR2).Molecular biology reports · 2024Article
- c-Rel is a Novel Oncogene in Lung Squamous Cell Carcinoma Regulating Cell Proliferation and Migration.Journal of Cancer · 2024Article
- DNA-dependent protein kinase catalytic subunit binds to the transactivation domain 1 of NF-κB p65.Biochemistry and biophysics reports · 2023Article
- NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer.Cell death & disease · 2023Article
- Nano-TRAIL: a promising path to cancer therapy.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer Cells.International journal of molecular sciences · 2022Article
- Single cell sequencing revealed the mechanism of PD-1 resistance affected by the expression profile of peripheral blood immune cells in ESCC.Frontiers in immunology · 2022Article
- NF-κB and Pancreatic Cancer; Chapter and Verse.Cancers · 2021Review
- Constitutive expression of c-REL in uveal melanoma patients: correlation with clinicopathological parameters and patient outcome.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2020Article
- ROCK2 mediates osteosarcoma progression and TRAIL resistance by modulating O-GlcNAc transferase degradation.American journal of cancer research · 2020Article
- Review
- Constitutive activation and overexpression of NF-κB/c-Rel in conjunction with p50 contribute to aggressive tongue tumorigenesis.Oncotarget · 2018Article
- Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells.Clinical and experimental medicine · 2018Article
- TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno Crosstalk Leading to TRAIL Resistance of Pancreatic Cancer Cell Lines.International journal of molecular sciences · 2018Article
- GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells.PloS one · 2018Article
- The role of NF-κB and miRNA in oral cancer and cancer stem cells with or without HPV16 infection.PloS one · 2018Article
- Identification and characterization of two functional variants in the human longevity gene FOXO3.Nature communications · 2017Article
- High-depth, high-accuracy microsatellite genotyping enables precision lung cancer risk classification.Oncogene · 2017Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-κB signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-κB activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-κB-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-κB complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL-induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.
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