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Inhibition of proteasome deubiquitinase activity : a strategy to overcome resistance to conventional proteasome inhibitors?

Authors :
Selvaraju, Karthik
Mazurkiewicz, Magdalena
Wang, Xin
Gullbo, Joachim
Linder, Stig
D'Arcy, Padraig
Selvaraju, Karthik
Mazurkiewicz, Magdalena
Wang, Xin
Gullbo, Joachim
Linder, Stig
D'Arcy, Padraig
Publication Year :
2015

Abstract

Although more traditionally associated with degradation and maintenance of protein homeostasis, the ubiquitin-proteasome system (UPS) has emerged as a critical component in the regulation of cancer cell growth and survival. The development of inhibitors that block the proteolytic activities of the proteasome have highlighted its suitability as a bona fide anti-cancer drug target. However, key determinants including the development of drug resistance and dose-limiting toxicity call for the identification of alternative components of the UPS for novel drug targeting. Recently the deubiquitinases (DUBS), a diverse family of enzymes that catalyze ubiquitin removal, have attracted significant interest as targets for the development of next generation UPS inhibitors. In particular, pharmacological inhibition of the proteasomal cysteine DUBs (i.e., USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells and inhibit tumour growth in several in vivo models. In the current review we focus on the modes of action of proteasome DUB inhibitors and discus the potential of DUB inhibitors to circumvent acquired drug resistance and provide a therapeutic option for the treatment of cancer.

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1234152037
Document Type :
Electronic Resource
Full Text :
https://doi.org/10.1016.j.drup.2015.06.001