Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells.
Open accessAbstract
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 (eIF2alpha), 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 eIF2alpha. 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-eIF2alpha-dependent mechanism to eliminate protein aggregates and alleviate proteotoxic stress.
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Previous studies have shown that inhibition of the proteasome system induces autophagy in vivo and in vitro.
“Previous studies have shown that inhibition of the proteasome system induces autophagy in vivo and in vitro (Iwata et al., 2005; Pandey et al., 2007; Zhu et al., 2010).”
From Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy (2020) · cites this paper as Zhu et al., 2010
The Abstract (page not provided) reports that proteasome inhibition promoted autophagy in cultured human prostate cancer cells and mouse embryonic fibroblasts, supporting the in vitro portion. The study does not report an in vivo test, so Zhu et al. does not support that portion of the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn a previous study, inhibition of the proteasome by specific silencing of a proteasome subunit stimulated increases in Atg5 and Atg7 levels.
“In a previous study, inhibition of the proteasome by specific silencing of a proteasome subunit also stimulated increases in Atg5 and Atg7 levels (Zhu et al., 2010).”
From Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy (2020) · cites this paper as Zhu et al., 2010
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- Authors
- Zhu, K., Dunner, K., & McConkey, D. J.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- McConkey, D J
- Venue
- Oncogene
- Published
- 2009-11-02
- Volume
- 29
- Issue
- 3
- Pages
- 451-462
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2809784
- OpenAlex
- W2158892689
- Cited by
- 338
- References
- 46
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 14 · 2023: 18 · 2022: 18 · 2021: 15 · 2020: 18 · 2019: 21 · 2018: 21 · 2017: 16 · 2016: 26 · 2015: 27 · 2014: 28 · 2013: 31 · 2012: 29
- FWCI
- 15.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- AstraZeneca
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- School of Medicine, Indiana University
- National Cancer Institute (CA-16672, R01CA127494, P30CA016672)
- DOD Prostate Cancer Research Program
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- proteasome inhibitors, autophagy, prostate cancer, eIF2α phosphorylation, ATG5, ATG7, protein aggregation, proteotoxic stress, unfolded protein response, ubiquitin-proteasome system, cytoprotection, autophagic flux
- MeSH terms
- Bortezomib, Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Boronic Acids, Cell Line, Cell Survival, Humans, Lactones, Lysosomes, Male, Microtubule-Associated Proteins, Phagosomes, Prostatic Neoplasms, Protease Inhibitors, Pyrazines, Pyrroles, Immunoblotting, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Ubiquitin-Activating Enzymes, Cell Line, Tumor, Microscopy, Electron, Transmission, Proteasome Endopeptidase Complex, Proteasome Inhibitors
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