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Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB

Oncogene volume 35, pages 3399–3409 (2016)Cite this article

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Abstract

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.

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Acknowledgements

We are grateful to Marina Gernold, Martina Keith, Katarina Duglova and Scott Oliver for excellent technical assistance. We thank Sylvia Kaden for technical assistance during electron microscopy. We thank the tissue bank of the Center for National Tumor Disease (NCT, Heidelberg, Germany) for providing CRC tissues, and Sarah Meßnard and David Jansen for technical assistance during immunohistochemistry. This study was supported by a grant from the Manfred-Stolte-Foundation to WR, and by the Rahel Goitein-Straus Program of the Medical Faculty of Heidelberg (fellowship to MOM).

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Authors and Affiliations

  1. Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    M Oliver Metzig, D Fuchs, P Schirmacher & W Roth

  2. Molecular Tumor Pathology, German Cancer Research Center, Heidelberg, Germany

    M Oliver Metzig, D Fuchs, K E Tagscherer & W Roth

  3. Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany

    H-J Gröne

  4. Institute of Pathology, University Medical Center Mainz, Mainz, Germany

    W Roth

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Correspondence to W Roth.

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Oliver Metzig, M., Fuchs, D., Tagscherer, K. et al. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene 35, 3399–3409 (2016). https://doi.org/10.1038/onc.2015.398

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