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Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells

Oncogene volume 22, pages 1807–1816 (2003)Cite this article

Abstract

Cytokines such as Fas-ligand (Fas-L) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) can induce human colon cancer cell apoptosis through engagement of their death domain receptors. All the cancer cells are not sensitive to these cytokines. We have shown recently that low doses of cytotoxic drugs could restore TRAIL-induced cell death in resistant colon cancer cell lines. The present work further explores the death pathway triggered by the cytotoxic drug/TRAIL combination in HT-29 colon cancer cells (www.alexis-corp.com). Clinically relevant concentrations of cisplatin, doxorubicin and 5-fluorouracil synergize with TRAIL to trigger HT-29 cell death. Activation of this pathway leads to apoptosis that involves both caspases and the mitochondria. An increased recruitment of Fas-associated death domain (FADD) and procaspase-8 to the TRAIL-induced death-inducing signaling complex (DISC) was shown in cells exposed to anticancer drugs. Following caspase-8 activation at the DISC level, the mitochondria-dependent death pathway is activated, as demonstrated by the cleavage of Bid, the dissipation of ΔΨm, the release of mitochondrial proteins in the cytosol and the inhibitory effect of Bcl-2 expression. Importantly, besides mitochondrial potentiation, we show here that cytotoxic drugs sensitize HT-29 colon cancer cells to TRAIL-induced cell death by enhancing FADD and procaspase-8 recruitment to the DISC, a novel mechanism whose efficacy could depend partly on Bcl-2 expression level.

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Acknowledgements

This work was supported by grants from the Nièvre committee (MTDB) and special grants (ES) from la Ligue Nationale Contre le Cancer. SL is supported by la Ligue Nationale Contre le Cancer.

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Author notes

  1. Sandrine Lacour and Olivier Micheau: Both authors contributed equally to this work.

Authors and Affiliations

  1. INSERM U517, IFR 100, Faculties of Medicine and Pharmacy, 7 boulevard Jeanne d'Arc, Dijon, 21033, Cedex, France

    Sandrine Lacour, Arlette Hammann, Véronique Drouineaud, Eric Solary & Marie-Thérèse Dimanche-Boitrel

  2. Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Epalinges, CH-1066, Switzerland

    Olivier Micheau & Jurg Tschopp

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  1. Sandrine Lacour
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Correspondence to Marie-Thérèse Dimanche-Boitrel.

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Lacour, S., Micheau, O., Hammann, A. et al. Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene 22, 1807–1816 (2003). https://doi.org/10.1038/sj.onc.1206127

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