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000129240 0247_ $$2doi$$a10.1038/onc.2015.398
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000129240 1001_ $$0P:(DE-He78)68ae5c66558436217ba098760e466305$$aOliver Metzig, Marie$$b0$$eFirst author$$udkfz
000129240 245__ $$aInhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB.
000129240 260__ $$aBasingstoke$$bNature Publ. Group$$c2016
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000129240 520__ $$aResistance 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.
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000129240 650_7 $$2NLM Chemicals$$aAntimetabolites, Antineoplastic
000129240 650_7 $$2NLM Chemicals$$aNF-kappa B
000129240 650_7 $$2NLM Chemicals$$aOligopeptides
000129240 650_7 $$2NLM Chemicals$$aReceptors, Tumor Necrosis Factor, Type I
000129240 650_7 $$2NLM Chemicals$$aTumor Necrosis Factor-alpha
000129240 650_7 $$2NLM Chemicals$$abenzyloxycarbonyl-valyl-alanyl-aspartic acid
000129240 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aRIPK1 protein, human
000129240 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aReceptor-Interacting Protein Serine-Threonine Kinases
000129240 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aCaspases
000129240 650_7 $$0U3P01618RT$$2NLM Chemicals$$aFluorouracil
000129240 7001_ $$0P:(DE-He78)f31d93a5acf6105d99da2e980f8065e3$$aFuchs, D.$$b1$$udkfz
000129240 7001_ $$0P:(DE-He78)55bdae24f65a1c0e58c6d721e968c3f4$$aTagscherer, Katrin$$b2$$udkfz
000129240 7001_ $$0P:(DE-HGF)0$$aGröne, H-J$$b3
000129240 7001_ $$aSchirmacher, P.$$b4
000129240 7001_ $$0P:(DE-He78)6c54d919bb3371b6d7f277e2c6262a4a$$aRoth, Wilfried$$b5$$eLast author$$udkfz
000129240 773__ $$0PERI:(DE-600)2008404-3$$a10.1038/onc.2015.398$$gVol. 35, no. 26, p. 3399 - 3409$$n26$$p3399 - 3409$$tOncogene$$v35$$x1476-5594$$y2016
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