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Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways

Oncogene volume 20, pages 2122–2133 (2001)Cite this article

Abstract

Tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines that promotes apoptosis. TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells. The objectives of this study are to investigate the intracellular mechanisms by which TRAIL induces apoptosis. The death receptor Fas, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8. It is unclear whether FADD is required for TRAIL-induced apoptosis. Here we show that the signaling complex of DR4/DR5 is assembled in response to TRAIL binding. FADD and caspase-8, but not caspase-10, are recruited to the receptor, and cells deficient in either FADD or caspase-8 blocked TRAIL-induced apoptosis. In addition, TRAIL initiates the activation of caspases, the loss of mitochondrial transmembrane potential (Δψm), the cleavage of BID, and the redistribution of mitochondrial cytochrome c. Treatment of Jurkat cells with cyclosporin A delayed TRAIL-induced Δψm, caspase-3 activation and apoptosis. Similarly, Overexpression of Bcl-2 or Bcl-XL delayed, but did not inhibit, TRAIL-induced Δψm and apoptosis. In contrast, XIAP, cowpox virus CrmA and baculovirus p35 inhibited TRAIL-induced apoptosis. These data suggest that death receptors (DR4 and DR5) and Fas receptors induced apoptosis through identical signaling pathway, and TRAIL-induced apoptosis via both mitochondrial-dependent and -independent pathways.

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Acknowledgements

We extend our sincere thanks to Craig Thompson (University of Pennsylvania, Philadelphia, PA, USA) and Stanley Korsmeyer (Dana-Farber Cancer Institute, Boston, MA, USA) for providing the Bcl-XL and Bcl-2 expression vector, respectively. We are grateful to Dr John Blennis (Harvard Medical School, Boston, MA, USA) for providing caspase-8 and FADD deficient Jurkat cells. We also thank Dr Vishva Dixit (Genentech, South San Francisco, CA, USA) for providing dominant negative FADD and caspase-8 constructs.

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  1. Department of Pharmaceutical Sciences, University of Maryland - School of Pharmacy, 20 N Pine Street, Baltimore, 21201, Maryland MD, USA

    Ayoub Suliman, Arh Lam & Rakesh K Srivastava

  2. Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Rakesh Datta

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Suliman, A., Lam, A., Datta, R. et al. Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20, 2122–2133 (2001). https://doi.org/10.1038/sj.onc.1204282

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