Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-[kappa]B
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 i...
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| Hauptverfasser: | , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2016
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| In: |
Oncogene
Year: 2015, Jahrgang: 35, Heft: 26, Pages: 3399-3409 |
| ISSN: | 1476-5594 |
| DOI: | 10.1038/onc.2015.398 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/onc.2015.398
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| Verfasserangaben: | M. Oliver Metzig, D. Fuchs, K.E. Tagscherer, H.-J. Gröne, P. Schirmacher and W. Roth |
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| 245 | 1 | 0 | |a Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-[kappa]B |c M. Oliver Metzig, D. Fuchs, K.E. Tagscherer, H.-J. Gröne, P. Schirmacher and W. Roth |
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| 246 | 3 | 3 | |a Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-alpha-dependent necroptosis driven by RIP1 kinase and NF-kappa B |
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| 500 | |a Gesehen am 04.05.2020 | ||
| 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. | ||
| 534 | |c 2015 | ||
| 650 | 4 | |a Animals | |
| 650 | 4 | |a Antimetabolites, Antineoplastic | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Caspases | |
| 650 | 4 | |a Cell Line, Tumor | |
| 650 | 4 | |a Colonic Neoplasms | |
| 650 | 4 | |a Fluorouracil | |
| 650 | 4 | |a HCT116 Cells | |
| 650 | 4 | |a HT29 Cells | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Immunoblotting | |
| 650 | 4 | |a Immunohistochemistry | |
| 650 | 4 | |a Male | |
| 650 | 4 | |a Mice, Nude | |
| 650 | 4 | |a Microscopy, Electron | |
| 650 | 4 | |a Necrosis | |
| 650 | 4 | |a NF-kappa B | |
| 650 | 4 | |a Oligopeptides | |
| 650 | 4 | |a Receptor-Interacting Protein Serine-Threonine Kinases | |
| 650 | 4 | |a Receptors, Tumor Necrosis Factor, Type I | |
| 650 | 4 | |a Reverse Transcriptase Polymerase Chain Reaction | |
| 650 | 4 | |a RNA Interference | |
| 650 | 4 | |a Tumor Burden | |
| 650 | 4 | |a Tumor Necrosis Factor-alpha | |
| 650 | 4 | |a Xenograft Model Antitumor Assays | |
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