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The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells

Oncogene volume 22, pages 4953–4963 (2003)Cite this article

Abstract

We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosis-inducing ligand (TRAIL)-induced apoptosis irrespective of Bcl-xL overexpression. PS-341 treatment by itself does not affect the levels of Bax, Bak, caspases 3 and 8, c-Flip or FADD, but elevates levels of TRAIL receptors DR4 and DR5. This increase in receptor protein levels is associated with the ubiquitination of the DR5 protein. When PS-341 is combined with TRAIL, the levels of activated caspase 8 and cleaved Bid are substantially increased. In Bax-negative TRAIL-resistant HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of the mitochondrial pathway and causes SMAC and cytochrome c release followed by apoptosis. Similarly, murine embryonic fibroblasts lacking Bax undergo apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are significantly resistant. Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing the cleavage of caspase 8, causing Bak-dependent release of mitochondrial proapoptotic proteins.

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Abbreviations

TRAIL:

TNF-like apoptosis-inducing ligand

DISC:

death-inducing signaling complex

PARP:

polyADP ribose polymerase

MEF:

murine embryonic fibroblasts

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Acknowledgements

We thank Dr Sookhee Bang (National Institutes of Health, Bethesda, MD, USA) for preparing TRAIL protein. The HC-4 and HCT-116 cells were kindly provided by both Drs B Vogelstein (Johns Hopkins University, Baltimore MD, USA) and M Perucho (Burnham Institute, San Diego, CA, USA). We also thank Dr David Baltimore (California Institute of Technology, Pasadena, CA, USA) for providing the Fkp3-caspase 8 (180) cDNA construct. The LNCaP-Bcl-xL cells were a gift of Dr Ralph Buttyan (Columbia Presbyterian Medical Center, New York, NY, USA). We are grateful to Dr R Hakem (Ontario Cancer Institute, Toronto, Canada) for providing the caspase 9-deficient fibroblasts. We thank Dr Daniel Chan for performing the Calculyn analysis, examining synergism between these two compounds. The NF6 antibody against c-FLIP was a kind gift of Dr Marcus Peter, Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, USA. We thank Dr Mathias Treier, Max Delbrueck Centrum, Berlin, Germany for the HA-tagged ubiquitin expression construct. The continued support of this project by Millenium Corp. is highly appreciated. Wei-Xing Zong is a recipient of the Cancer Research Institute (CRI) postdoctoral fellowship.

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Authors and Affiliations

  1. Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, 80262, CO, USA

    Thomas R Johnson, Kimberley Stone, Malti Nikrad, Tammie Yeh, Alexandre Nesterov & Andrew S Kraft

  2. Department of Medicine, Cancer Biology, and Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104, PA, USA

    Wei-Xing Zong & Craig B Thompson

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  1. Thomas R Johnson
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Correspondence to Andrew S Kraft.

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This work was supported by Department of Defense Grant DAMD17-99-1-9516 to ASK

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Johnson, T., Stone, K., Nikrad, M. et al. The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 22, 4953–4963 (2003). https://doi.org/10.1038/sj.onc.1206656

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