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TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP

Oncogene volume 28, pages 2257–2265 (2009)Cite this article

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of cell death in several cancer cells, but many cells are resistant to TRAIL. The mechanism that determines sensitivity to TRAIL-killing is still elusive. Here we report that deletion of TAK1 kinase greatly increased activation of caspase-3 and cell death after TRAIL stimulation in keratinocytes, fibroblasts and cancer cells. Although TAK1 kinase is involved in NF-κB pathway, ablation of NF-κB did not alter sensitivity to TRAIL. We found that TRAIL could induce accumulation of reactive oxygen species (ROS) when TAK1 was deleted. Furthermore, we found that TAK1 deletion induced TRAIL-dependent downregulation of cIAP, which enhanced activation of caspase-3. These results show that TAK1 deletion facilitates TRAIL-induced cell death by activating caspase through ROS and downregulation of cIAP. Thus, inhibition of TAK1 can be an effective approach to increase TRAIL sensitivity.

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Acknowledgements

We thank Drs Akira, Karin, Ballard and Wang for materials. This work was supported by a grant (GM068812) from NIH to JN-T.

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Authors and Affiliations

  1. Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan

    S Morioka, T Kajino & K Matsumoto

  2. Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC, USA

    S Morioka, E Omori, R Kajino-Sakamoto & J Ninomiya-Tsuji

  3. Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency, Japan

    K Matsumoto

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  1. S Morioka
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Correspondence to J Ninomiya-Tsuji.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Morioka, S., Omori, E., Kajino, T. et al. TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP. Oncogene 28, 2257–2265 (2009). https://doi.org/10.1038/onc.2009.110

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