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Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis

Oncogene volume 22, pages 2674–2679 (2003)Cite this article

Abstract

Thapsigargin (TG), by inducing perturbations in cellular Ca2+ homeostasis, can induce apoptosis, but the molecular mechanisms remain to be fully elucidated. We have recently reported that TG-induced apoptosis appears to involve the DR5-dependent apoptotic pathway that cross talks with the mitochondrial pathway via TG-induced Bid cleavage. In this study, we have utilized Bax-proficient and -deficient HCT116 human colon cancer cells to investigate the effect of Bax deficiency on TG-induced apoptosis and TG regulation of the DR5 and mitochondrial pathways. Our results indicate that Bax-deficient cells are less sensitive to undergo apoptosis following TG treatment. Our results further demonstrate that TG-induced apoptosis is coupled with DR5 upregulation and caspases 8 and 3 activation, as well as Bid cleavage in both Bax-proficient and -deficient cells, although caspase 3 activation was reduced in Bax-deficient cells. TG also promoted the release of cytochrome c into cytosol and caspase 9 activation in Bax-proficient cells but not in Bax-deficient cells. These findings suggest that although Bax is not absolutely required for death receptor (DR)-dependent signals, it appears to be a key molecule in TG-regulated mitochondrial events. Bax-deficient cells were relatively more resistant to Apo2L/TRAIL than the Bax-proficient counterparts. However, the combination of Apo2L/TRAIL and TG was more effective in mediating apoptosis in both Bax-proficient and -deficient cells and that was coupled with activation of caspases 8 and 3. Although both agents in combination also induced cytochrome c release into cytosol and caspase 9 activation in Bax-proficient cells, these events were abrogated in Bax-deficient cells. Our results thus suggest that the combination of Apo2L/TRAIL and TG appears to bypass the Bax deficiency-induced defects in the mitochondrial (intrinsic) pathway by engaging the DR5-dependent apoptotic signals (extrinsic pathway).

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Acknowledgements

We thank Dr Avi Ashkenazi and Genentech for a generous supply of Apo2L/TRAIL and Dr Bert Vogelstein for kindly providing the Bax-proficient and -deficient HCT116 cells. This work was supported in part by United States Army Prostate Cancer Research Program grant DAMD 170010722 and by NIH Grant CA89043.

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  1. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, 13210, NY, USA

    Qin He, JoAnne Montalbano, Chad Corcoran, Weixin Jin, Ying Huang & M Saeed Sheikh

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  1. Qin He
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Correspondence to M Saeed Sheikh.

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He, Q., Montalbano, J., Corcoran, C. et al. Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis. Oncogene 22, 2674–2679 (2003). https://doi.org/10.1038/sj.onc.1206363

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