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Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and -deficient cells

Oncogene volume 23, pages 2554–2558 (2004)Cite this article

Abstract

Apo2L/TRAIL (tumor necrosis factor-related apoptosis inducing ligand (TRAIL), also known as Apo2L) is a potentially important anticancer agent awaiting clinical trials. Unfortunately, however, some cancer cells exhibit resistance to Apo2L/TRAIL, which could limit the use of this potentially promising anticancer agent. Although the molecular basis of the inherent or acquired resistance to Apo2L/TRAIL remains unclear, previous studies indicate that Bax deficiency can confer resistance to Apo2L/TRAIL. Proteasome inhibition is also emerging as a promising therapeutic strategy to manage human malignancies. Here, we report that proteasome inhibitor MG132 upregulates Apo2L/TRAIL death receptor 5 expression in both Bax-proficient and -deficient HCT116 cells. MG132 effectively cooperated with Apo2L/TRAIL to induce apoptosis in both Bax-proficient and -deficient cells that was coupled with caspases-8 and -3 activation and Bid cleavage. Although both agents in combination also induced cytochrome c and Smac release from mitochondria into cytosol and activated caspase-9 in Bax-proficient cells, their effects on these events were significantly diminished in Bax-deficient cells. These results suggest that Bax is not absolutely required for death receptor 5-dependent apoptotic signals and MG132 by upregulating DR5 effectively cooperates with Apo2L/TRAIL to overcome Bax deficiency-induced resistance to Apo2L/TRAIL. Our results have important clinical implications in that the use of Apo2L/TRAIL and proteasome inhibitors in combination could prove to be a novel therapeutic strategy to manage the Apo2L/TRAIL-resistant tumors.

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Acknowledgements

We are thankful to Dr Avi Ashkenazi and Genentech for generous supply of Apo2L/TRAIL and Dr Bert Vogelstein for kindly providing the Bax-proficient and Bax-deficient HCT116 cells. This work was supported in part by United States Army Prostate Cancer Research Program Grant DAMD 170010722 and by NIH Grants CA89043, CA86945 and DK062136.

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

    Qin He, 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., Huang, Y. & Sheikh, M. Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and -deficient cells. Oncogene 23, 2554–2558 (2004). https://doi.org/10.1038/sj.onc.1207351

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