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Bax translocation is crucial for the sensitivity of leukaemic cells to etoposide-induced apoptosis

Oncogene volume 20, pages 4817–4826 (2001)Cite this article

Abstract

Bax translocation from cytosol to mitochondria is believed to be a crucial step for triggering cytochrome c release from mitochondria. However, it is unclear whether Bax translocation is associated with Bax induction by DNA damaging agents. The induction of Bax in response to DNA damaging agents has been considered to be linked with p53. In this study, we used the p53 negative human chronic myeloid leukaemia K562 cell line. Bax up-regulation occurred at the whole cell level after DNA damage induced by etoposide. However, after incubation with etoposide, Bax failed to translocate to mitochondria and as a result, the apoptotic process was blocked. A Bax stable transfectant, the K/Bax cell line, expressed more Bax protein in the cytosol, mitochondria and nuclei. This Bax overexpression induced cytochrome c release, a reduction of cytochrome c oxidase activity and mitochondrial membrane potential (ΔΨm). However, Bax-induced apoptosis was blocked downstream of mitochondria in K562 cells. The increased levels of mitochondrial Bax sensitized cells to etoposide-induced activation of caspases-2, -3 and -9 and apoptosis. However, after transient transfection with the Apaf-1 gene, K/Bax cells were sensitized to etoposide-induced caspase activation and apoptosis to a larger extent compared with Bax or Apaf-1 transfection alone. We therefore conclude that two mechanisms contribute to the resistance of K562 cells to etoposide-induced apoptosis; firstly failure of Bax targeting to mitochondria and, secondly, deficiency of Apaf-1. Uncoupling of Bax translocation from Bax induction can occur in response to etoposide-induced DNA damage.

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Acknowledgements

This project was supported by Leukaemia Research Fund (9946) to SM Kelsey and L Jia.

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Authors and Affiliations

  1. Department of Haematology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London, E1 2AD, UK

    Li Jia, Yasmeen Patwari, Adrian C Newland & Stephen M Kelsey

  2. Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, PA, USA

    Srinivasa M Srinivasula, Teresa Fernandes-Alnemri & Emad S Alnemri

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  1. Li Jia
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  2. Yasmeen Patwari
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Correspondence to Li Jia.

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Jia, L., Patwari, Y., Srinivasula, S. et al. Bax translocation is crucial for the sensitivity of leukaemic cells to etoposide-induced apoptosis. Oncogene 20, 4817–4826 (2001). https://doi.org/10.1038/sj.onc.1204628

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