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Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells

Oncogene volume 29, pages 451–462 (2010)Cite this article

Abstract

The ubiquitin-proteasome and lysosome-autophagy pathways are the two major intracellular protein degradation systems that work cooperatively to maintain homeostasis. Proteasome inhibitors (PIs) have clinical activity in hematological tumors, and inhibitors of autophagy are also being evaluated as potential antitumor therapies. In this study, we found that chemical PIs and small interfering RNA-mediated knockdown of the proteasome's enzymatic subunits promoted autophagosome formation, stimulated autophagic flux, and upregulated expression of the autophagy-specific genes (ATGs) (ATG5 and ATG7) in some human prostate cancer cells and immortalized mouse embryonic fibroblasts (MEFs). Upregulation of ATG5 and ATG7 only occurred in cells displaying PI-induced phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α), an important component of the unfolded protein responses. Furthermore, PIs did not induce autophagy or upregulate ATG5 in MEFs expressing a phosphorylation-deficient mutant form of eIF2α. Combined inhibition of autophagy and the proteasome induced an accumulation of intracellular protein aggregates reminiscent of neuronal inclusion bodies and caused more cancer cell death than blocking either degradation pathway alone. Overall, our data show that proteasome inhibition activates autophagy through a phospho-eIF2α-dependent mechanism to eliminate protein aggregates and alleviate proteotoxic stress.

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Acknowledgements

This work was supported by a grant from the Department of Defense Prostate Cancer Research Program (PC050288). The TEM studies were supported by the MD Anderson Cancer Center Support Grant (CA16672) to the High Resolution Electron Microscopy Facility. We also acknowledge Dr Woonyoung Choi and Maosheng Huang's help with the array data analyses.

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Zhu, K Dunner Jr & D J McConkey

  2. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Zhu & D J McConkey

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  1. K Zhu
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  2. K Dunner Jr
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  3. D J McConkey
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Correspondence to D J McConkey.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Zhu, K., Dunner, K. & McConkey, D. Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 29, 451–462 (2010). https://doi.org/10.1038/onc.2009.343

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