TY  - JOUR
AU  - Oliver Metzig, Marie
AU  - Fuchs, D.
AU  - Tagscherer, Katrin
AU  - Gröne, H-J
AU  - Schirmacher, P.
AU  - Roth, Wilfried
TI  - Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB.
JO  - Oncogene
VL  - 35
IS  - 26
SN  - 1476-5594
CY  - Basingstoke
PB  - Nature Publ. Group
M1  - DKFZ-2017-05245
SP  - 3399 - 3409
PY  - 2016
AB  - 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.
KW  - Antimetabolites, Antineoplastic (NLM Chemicals)
KW  - NF-kappa B (NLM Chemicals)
KW  - Oligopeptides (NLM Chemicals)
KW  - Receptors, Tumor Necrosis Factor, Type I (NLM Chemicals)
KW  - Tumor Necrosis Factor-alpha (NLM Chemicals)
KW  - benzyloxycarbonyl-valyl-alanyl-aspartic acid (NLM Chemicals)
KW  - RIPK1 protein, human (NLM Chemicals)
KW  - Receptor-Interacting Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - Caspases (NLM Chemicals)
KW  - Fluorouracil (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26522725
DO  - DOI:10.1038/onc.2015.398
UR  - https://inrepo02.dkfz.de/record/129240
ER  -