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A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma

Oncogene volume 27, pages 6012–6022 (2008)Cite this article

Abstract

A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAIL-induced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the death-inducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAIL-induced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.

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Acknowledgements

We thank Valérie Nicolas for her assistance in confocal microscopy and G Ortiz-Ferron for providing FLBid-GFP vector. This work was supported by INSERM and the Ligue Nationale contre le Cancer (équipe labellisée). Olivia Ndozangue-Touriguine was a recipient of a fellowship from the Ministry of Research and Education and is a recipient of an ARC fellowship for her fourth year of PhD.

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Authors and Affiliations

  1. INSERM U749, Faculté de Pharmacie, Châtenay-Malabry, Hauts-de-Seine, France

    O Ndozangue-Touriguine, J Bertoglio & J Bréard

  2. UMR 891 INSERM, Institut Paoli-Calmettes, Marseille, Bouches-du-Rhône, France

    M Sebbagh

  3. INSERM U866, Dijon, Côte d'Or, France

    D Mérino & O Micheau

  4. University of Bourgogne, Dijon, Côte d'Or, France

    D Mérino & O Micheau

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  1. O Ndozangue-Touriguine
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Correspondence to J Bréard.

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Ndozangue-Touriguine, O., Sebbagh, M., Mérino, D. et al. A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma. Oncogene 27, 6012–6022 (2008). https://doi.org/10.1038/onc.2008.197

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