title: Molecular pathways: translational potential of deubiquitinases as drug targets.
abstract: The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS coupled with the clinical success of bortezomib for the treatment of multiple myeloma have made the UPS an obvious target for drug development. Deubiquitinases (DUB) are components of the UPS that encompass a diverse family of ubiquitin isopeptidases that catalyze the removal of ubiquitin moieties from target proteins or from polyubiquitin chains, resulting in altered signaling or changes in protein stability. Increasing evidence has implicated deregulation of DUB activity in the initiation and progression of cancer. The altered pattern of DUB expression observed in many tumors can potentially serve as a clinical marker for predicting disease outcome and therapy response. The finding of DUB overexpression in tumor cells suggests that they may serve as novel targets for the development of anticancer therapies. Several specific and broad-spectrum DUB inhibitors are shown to have antitumor activity in preclinical in vivo models with low levels of systemic toxicity. Future studies will hopefully establish the clinical potential for DUB inhibitors as a strategy to treat cancer.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm and Padraig.Darcy@ki.se.
authors.forename: Pádraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm and Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D061988:Proteasome Inhibitors; D025801:Ubiquitin; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex