title: Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?
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.
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, SE-581 85, Sweden.
authors.forename: Karthik
authors.initials: K
authors.lastname: Selvaraju
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mazurkiewicz
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, SE-581 85, Sweden.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 85, Sweden.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, SE-581 85, Sweden; Department of Oncology and Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, SE-581 85, Sweden. Electronic address: Padraig.Darcy@liu.se.
authors.forename: Pádraig
authors.initials: P
authors.lastname: D'Arcy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D064570:Ubiquitin-Specific Proteases
keywords: Apoptosis; Cancer therapeutics; DUB; Deubiquitinase; Proteasome; Small molecule inhibitors; α,β−Unsaturated ketones