Proteasome deubiquitinases as novel targets for cancer therapy

Int J Biochem Cell Biol. 2012 Nov;44(11):1729-38. doi: 10.1016/j.biocel.2012.07.011. Epub 2012 Jul 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Resistance, Neoplasm / drug effects
  • Endopeptidases / metabolism*
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • Neoplasms / therapy
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use


  • Proteasome Inhibitors
  • Endopeptidases
  • Proteasome Endopeptidase Complex