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c-FLIP inhibits chemotherapy-induced colorectal cancer cell death

Oncogene volume 25, pages 838–848 (2006)Cite this article

Abstract

c-FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5. We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan). Simultaneous downregulation of both c-FLIP splice forms c-FLIPL and c-FLIPS with siRNA synergistically enhanced chemotherapy-induced apoptosis in p53 wild-type (HCT116p53+/+, RKO), null (HCT116p53−/−) and mutant (H630) CRC cell lines. Furthermore, overexpression of c-FLIPL, but not c-FLIPS, potently inhibited apoptosis induced by chemotherapy in HCT116p53+/+ cells, suggesting that c-FLIPL was the more important splice form in mediating chemoresistance. In support of this, siRNA specifically targeted against c-FLIPL synergistically enhanced chemotherapy-induced apoptosis in a manner similar to the siRNA targeted against both splice forms. Inhibition of caspase 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy. Furthermore, we found that downregulating cell surface DR5, but not Fas, also inhibited apoptosis induced by FT siRNA and chemotherapy. Interestingly, these effects were not dependent on activation of DR5 by its ligand TRAIL. These results indicate that c-FLIP inhibits TRAIL-independent, DR5- and caspase 8-dependent apoptosis in response to chemotherapy in CRC cells. Moreover, targeting c-FLIP in combination with existing chemotherapies may have therapeutic potential for the treatment of CRC.

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Acknowledgements

This work was supported by: Cancer Research UK, the Medical Research Council, the Research and Development Office and the Department of Health and Social Services, Northern Ireland and the Ulster Cancer Foundation.

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  1. D B Longley and T R Wilson: These authors contributed to this work equally.

Authors and Affiliations

  1. Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK

    D B Longley, T R Wilson, M McEwan, W L Allen, U McDermott, L Galligan & P G Johnston

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  1. D B Longley
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  2. T R Wilson
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Correspondence to D B Longley.

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Longley, D., Wilson, T., McEwan, M. et al. c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene 25, 838–848 (2006). https://doi.org/10.1038/sj.onc.1209122

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