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| Home > Publications database > Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. > print |
| Home > Publications database > Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. > print |
| 001 | 129240 | ||
| 005 | 20240228143413.0 | ||
| 024 | 7 | _ | |a 10.1038/onc.2015.398 |2 doi |
| 024 | 7 | _ | |a pmid:26522725 |2 pmid |
| 024 | 7 | _ | |a 0950-9232 |2 ISSN |
| 024 | 7 | _ | |a 1476-5594 |2 ISSN |
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| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Oliver Metzig, Marie |0 P:(DE-He78)68ae5c66558436217ba098760e466305 |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. |
| 260 | _ | _ | |a Basingstoke |c 2016 |b Nature Publ. Group |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1524833112_15062 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Resistance towards the drug 5-fluorouracil (5-FU) is a key challenge in the adjuvant chemotherapy of colorectal cancer (CRC), and novel targeted approaches are required to improve the therapeutic outcome. Necroptosis is a recently discovered form of programmed cell death, which depends on receptor interacting protein 1 (RIP1) and particularly occurs under caspase-deficient conditions. The targeted induction of necroptosis represents a promising strategy to overcome apoptosis resistance in cancer. The aim of this study was to systematically explore the usage of pan-caspase inhibitors to sensitize resistant CRC cells for 5-FU. We found that pan-caspase inhibitors facilitated 5-FU-induced necroptosis, which was mediated by autocrine secretion of tumor necrosis factor α (TNF-α). TNF-α production was driven by nuclear factor κB (NF-κB) and required RIP1 kinase. In vivo xenograft experiments showed that the novel pan-caspase inhibitor IDN-7314 in combination with 5-FU synergistically blocked tumor growth. Ex vivo experiments with fresh human CRC tissue specimens further indicated that a subgroup of patients could benefit from combinatory treatment. Thereby, elevated levels of secreted TNF-α and expression of components of the necroptotic pathway might help to predict the sensitivity to pro-necroptotic therapies. Together, our results shed new light on the molecular regulation of necroptosis by NF-κB and RIP1. Moreover, we identify necroptotic cell death as an important effector mechanism of 5-FU-mediated anti-tumoral activity. On the basis of this study, we propose pan-caspase inhibitors as a novel approach in the adjuvant chemotherapy of CRC. |
| 536 | _ | _ | |a 317 - Translational cancer research (POF3-317) |0 G:(DE-HGF)POF3-317 |c POF3-317 |f POF III |x 0 |
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| 650 | _ | 7 | |a Antimetabolites, Antineoplastic |2 NLM Chemicals |
| 650 | _ | 7 | |a NF-kappa B |2 NLM Chemicals |
| 650 | _ | 7 | |a Oligopeptides |2 NLM Chemicals |
| 650 | _ | 7 | |a Receptors, Tumor Necrosis Factor, Type I |2 NLM Chemicals |
| 650 | _ | 7 | |a Tumor Necrosis Factor-alpha |2 NLM Chemicals |
| 650 | _ | 7 | |a benzyloxycarbonyl-valyl-alanyl-aspartic acid |2 NLM Chemicals |
| 650 | _ | 7 | |a RIPK1 protein, human |0 EC 2.7.11.1 |2 NLM Chemicals |
| 650 | _ | 7 | |a Receptor-Interacting Protein Serine-Threonine Kinases |0 EC 2.7.11.1 |2 NLM Chemicals |
| 650 | _ | 7 | |a Caspases |0 EC 3.4.22.- |2 NLM Chemicals |
| 650 | _ | 7 | |a Fluorouracil |0 U3P01618RT |2 NLM Chemicals |
| 700 | 1 | _ | |a Fuchs, D. |0 P:(DE-He78)f31d93a5acf6105d99da2e980f8065e3 |b 1 |u dkfz |
| 700 | 1 | _ | |a Tagscherer, Katrin |0 P:(DE-He78)55bdae24f65a1c0e58c6d721e968c3f4 |b 2 |u dkfz |
| 700 | 1 | _ | |a Gröne, H-J |0 P:(DE-HGF)0 |b 3 |
| 700 | 1 | _ | |a Schirmacher, P. |b 4 |
| 700 | 1 | _ | |a Roth, Wilfried |0 P:(DE-He78)6c54d919bb3371b6d7f277e2c6262a4a |b 5 |e Last author |u dkfz |
| 773 | _ | _ | |a 10.1038/onc.2015.398 |g Vol. 35, no. 26, p. 3399 - 3409 |0 PERI:(DE-600)2008404-3 |n 26 |p 3399 - 3409 |t Oncogene |v 35 |y 2016 |x 1476-5594 |
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