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

Abstract

The ubiquitin-proteasome system (UPS) is the primary mechanism controlling the degradation of damaged, unwanted or short-lived proteins in eukaryotic cells. In addition to protein homeostasis, the UPS has also emerged as a critical node in the regulation of signalling pathways implicated in the growth and survival of cancer cells. The absolute dependency of cancer cells on a functioning UPS has been exploited in the development of anti-cancer therapies as exemplified by development of proteasome inhibitors for the treatment of certain leukemic malignancies.Deubiquitinases (DUBs) are enzyme components of the UPS that catalyse re-editing of poly ubiquitin chains and/or removal of ubiquitin en bloc from target substrates leading to alterations in protein stability and/or downstream signalling. There is a growing recognition that targeting DUB activity may be a feasible option for the development of novel anti-cancer therapies. In particular inhibition of proteasomal cysteine DUBs (i.e. USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells leading to the accumulation of ubiquitinated proteins and proteotoxic stress. In this review we focus on the mechanisms of action of proteasome DUB inhibitors as well as the potential of such compounds to circumvent acquired drug resistance in cancer patients.

Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms

“…It is well established that inhibition of DUBs or the proteasome causes accumulation of ubiquitinated proteins [35]. Like in other cancer cells, we previously reported [27], we found that NiPT dose- and time-dependently induced accumulation of ubiquitinated proteins (Ubs) and proteasome substrate protein p27 in all CML cell lines we detected before the emergence of PARP cleavage (Fig.…”

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

“…USP14 and UCHL5 are cysteine proteases associated with the 19S regulatory subunit of the proteasome, with overlapping and sometimes complementary roles. Because of their slightly different deubiquitinating profiles, USP14 can either rescue proteins from proteasomal degradation by removing the polyubiquitin chain that facilitates proteasomal interaction or simply recycle the ubiquitin from a protein already commited to proteasomal interaction while UCHL5 more frequently facilitates proteasomal degradation [48–50]. However, these two structurally distinct deubiquitylases have overlapping and partially redundant functions so that they can compensate for each other’s activity [51, 52], as we have observed here.…”

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…455,456,458 Multitarget combination treatment Drug adverse effects and resistance are major obstacles in preclinical and clinical cancer treatments, and UPS inhibitors are no exception. [459][460][461] For drug adverse effects, the balance between effective dose and dose limiting toxicity is the principal contradiction. 462 The molecular mechanisms of anti-cancer drug resistance are also associated with tumor metabolism, the TME and CSCs, such as increasing drug metabolism and degradation of drug target proteins, enhance the tolerability of stressful TME conditions, and enhance the DNA damage response and antiapoptotic mechanisms of CSCs.…”