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Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Oncogene volume 25, pages 6582–6594 (2006)Cite this article

Abstract

In contrast to the initial notion that the biological activity of p14ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9- and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14ARF-induced apoptosis, suggesting that p14ARF-induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14ARF-induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wild-type HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14ARF-induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14ARF expression. These data indicate that p14ARF triggers apoptosis via a Bax/Bak-dependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14ARF-induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bak-independent mechanism.

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Acknowledgements

This work was supported by the Deutsche Krebshilfe Grant 10-2088-Da3 to PTD and PGH. We thank Ms Antje Richter and Ms Anja Richter for superb technical assistance. HCT116-Bax+/+ and HCT116 Bax−/− cells were generously provided by Dr Bert Vogelstein (Johns Hopkins Cancer Center, Baltimore, USA).

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Authors and Affiliations

  1. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Berlin-Buch, Germany

    P G Hemmati, D Güner, B Gillissen, J Wendt, C von Haefen, B Dörken & P T Daniel

  2. Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

    P G Hemmati, B Gillissen, B Dörken & P T Daniel

  3. Institute for Molecular Virology, Saint Louis University School of Medicine, St Louis, MO, USA

    G Chinnadurai

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  1. P G Hemmati
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Correspondence to P T Daniel.

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Hemmati, P., Güner, D., Gillissen, B. et al. Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells. Oncogene 25, 6582–6594 (2006). https://doi.org/10.1038/sj.onc.1209668

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