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Examining Proteasome Assembly with Recombinant Archaeal Proteasomes and Nondenaturing PAGE: The Case for a Combined Approach
Published on: December 17, 2016
Oncogenic addiction to high 26S proteasome level
Peter Tsvetkov1,2, Julia Adler1, Nadav Myers1
1Department of Molecular Genetics, Weizmann Institute of Science, 76100, Rehovot, Israel.
Abstract:
Proteasomes are large intracellular complexes responsible for the degradation of cellular proteins. The altered protein homeostasis of cancer cells results in increased dependency on proteasome function. The cellular proteasome composition comprises the 20S catalytic complex that is frequently capped with the 19S regulatory particle in forming the 26S proteasome. Proteasome inhibitors target the catalytic barrel (20S) and thus this inhibition does not allow the deconvolution of the distinct roles of 20S versus 26S proteasomes in cancer progression. We examined the degree of dependency of cancer cells specifically to the level of the 26S proteasome complex. Oncogenic transformation of human and mouse immortalized cells with mutant Ras induced a strong posttranscriptional increase of the 26S proteasome subunits, giving rise to high 26S complex levels. Depletion of a single subunit of the 19S RP was sufficient to reduce the 26S proteasome level and lower the cellular 26S/20S ratio. Under this condition the viability of the Ras-transformed MCF10A cells was severely compromised. This observation led us to hypothesize that cancer cell survival is dependent on maximal utilization of its 26S proteasomes. We validated this possibility in a large number of cancer cell lines and found that partial reduction of the 26S proteasome level impairs viability in all cancer cells examined and was not correlated with cell doubling time or reduction efficiency. Interstingly, normal human fibroblasts are refractory to the same type of 26S proteasome reduction. The suppression of 26S proteasomes in cancer cells activated the UPR and caspase-3 and cells stained positive with Annexin V. In addition, suppression of the 26S proteasome resulted in cellular proteasome redistribution, cytoplasm shrinkage, and nuclear deformation, the hallmarks of apoptosis. The observed tumor cell-specific addiction to the 26S proteasome levels sets the stage for future strategies in exploiting this dependency in cancer therapy.
Insights
Cancer cells depend on the 26S proteasome for survival. Reducing 26S proteasome levels impairs cancer cell viability, unlike in normal cells, suggesting a therapeutic target.
Area of Science:
- Cellular Biology
- Cancer Research
- Biochemistry
Background:
- Cancer cells exhibit altered protein homeostasis, increasing their reliance on proteasome function.
- The 26S proteasome, composed of the 20S catalytic core and 19S regulatory particle, is crucial for protein degradation.
- Current proteasome inhibitors target the 20S core, hindering the study of distinct 20S vs. 26S proteasome roles.
Purpose of the Study:
- To investigate cancer cell dependency specifically on the 26S proteasome complex.
- To determine if targeting the 26S proteasome level can be a viable cancer therapy strategy.
Main Methods:
- Oncogenic transformation of cells with mutant Ras to induce 26S proteasome subunit increase.
- Depletion of 19S regulatory particle subunits to alter the 26S/20S ratio.
- Assessing cancer cell viability upon 26S proteasome reduction.
- Evaluating apoptosis markers (UPR, caspase-3, Annexin V) and morphological changes.
Main Results:
- Mutant Ras transformation increased 26S proteasome levels in human and mouse cells.
- Depleting a single 19S subunit reduced 26S proteasome levels, compromising Ras-transformed cell viability.
- Partial reduction of 26S proteasomes impaired viability in all tested cancer cell lines but not normal fibroblasts.
- Suppression of 26S proteasomes induced apoptosis, characterized by UPR activation, caspase-3, Annexin V positivity, and cellular deformation.
Conclusions:
- Cancer cell survival is critically dependent on maximal 26S proteasome utilization.
- Normal fibroblasts are resistant to 26S proteasome reduction, highlighting tumor cell-specific dependency.
- The 26S proteasome level represents a promising therapeutic target for cancer treatment.
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