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Apoptosis

Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells

Leukemia volume 18, pages 1671–1680 (2004)Cite this article

Abstract

TRAIL-induced apoptosis has been considered a promising therapeutic approach for tumors that are resistant to chemotherapy, which is usually mediated via mitochondrial apoptotic cascades. Recent studies have shown that in certain cancer cells, TRAIL-mediated apoptosis is also dependent on mitochondrial involvement, suggesting that similar mechanisms of resistance to chemotherapy might be implicated in the resistance of tumor cells to TRAIL. We have used TRAIL-resistant leukemic cells that are deficient in both Bax and Bak to determine the roles of these Bcl-2 members in TRAIL-mediated apoptosis. Exposure of these cells to TRAIL did not have an impact on cell viability, although it induced the processing of caspase-3 to its active p20 subunit. The activity of the p20 caspase-3 appeared to be inhibited as no autoprocessing of this p20 subunit or cleavage of known caspase-3 substrates were detected. Also, in the absence of Bax and Bak, no release of mitochondrial apoptogenic proteins was observed following TRAIL treatment. Adenoviral transduction of the Bax, but not the Bak gene, to the Bax/Bak-deficient leukemic cells rendered them TRAIL-sensitive as assessed by enhanced apoptotic death and caspase-3 processing. These findings demonstrate preferential utilization of Bax over Bak in leukemic cell response to specific apoptotic stimulation.

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Acknowledgements

This work was supported by grants from The National Institute of Health Grant No. RO1 CA 84134 (HR), and The Department of Defense, Grant No. DAMD17-02-1-0552 (HR).

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  1. J Han and L A Goldstein: Both authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The University of Pittsburgh School of Medicine, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    J Han, L A Goldstein, A Rabinovitz, G-Q Wang & H Rabinowich

  2. Department of Plastic Surgery, The University of Pittsburgh School of Medicine, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    B R Gastman

  3. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    B Fang

  4. The University of Pittsburgh Cancer Institute, Pittsburgh, 15213, PA, USA

    H Rabinowich

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  1. J Han
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Correspondence to H Rabinowich.

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Han, J., Goldstein, L., Gastman, B. et al. Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells. Leukemia 18, 1671–1680 (2004). https://doi.org/10.1038/sj.leu.2403496

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