title: Proteasome deubiquitinases as novel targets for cancer therapy.
abstract: The ubiquitin-proteasome system (UPS) is a conserved pathway regulating numerous biological processes including protein turnover, DNA repair, and intracellular trafficking. Tumor cells are dependent on a functioning UPS, making it an ideal target for the development of novel anti-cancer therapies. The development of bortezomib (Velcade(®)) as a treatment for multiple myeloma and mantle cell lymphoma has verified this and suggests that targeting other components of the UPS may be a viable strategy for the treatment for cancer. We recently described a novel class of proteasome inhibitors that function by an alternative mechanism of action (D'Arcy et al., 2011). The small molecule b-AP15 blocks the deubiquitinase (DUB) activity of the 19S regulatory particle (19S RP) without inhibiting the proteolytic activities of the 20S core particle (20S CP). b-AP15 inhibits two proteasome-associated DUBs, USP14 and UCHL5, resulting in a rapid accumulation of high molecular weight ubiquitin conjugates and a functional proteasome shutdown. Interestingly, b-AP15 displays several differences to bortezomib including insensitivity to over-expression of the anti-apoptotic mediator Bcl-2 and anti-tumor activity in solid tumor models. In this review we will discuss the potential of proteasome deubiquitinase inhibitors as additions to the therapeutic arsenal against cancer.
authors: Institute for Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, 17176 Stockholm, Sweden. Padraig.Darcy@ki.se
authors: Pádraig
authors: P
authors: D'Arcy
authors: Stig
authors: S
authors: Linder
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D061988:Proteasome Inhibitors; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex