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Elevation of Proteasomal Substrate Levels Sensitizes Cells to Apoptosis Induced by Inhibition of Proteasomal Deubiquitinases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 10, e108839- p.Article in journal (Refereed) Published
Abstract [en]

Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system.

Place, publisher, year, edition, pages
2014. Vol. 9, no 10, e108839- p.
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-240146DOI: 10.1371/journal.pone.0108839ISI: 000345743700036PubMedID: 25286379OAI: diva2:776621
Available from: 2015-01-07 Created: 2015-01-05 Last updated: 2015-01-07Bibliographically approved

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