Targeting the ubiquitin–proteasome system for cancer therapy

Abstract

Introduction The ubiquitin–proteasome system (UPS) degrades 80 – 90% of intracellular proteins. Cancer cells take advantage of the UPS for their increased growth and decreased apoptotic cell death. Thus, the components that make up the UPS represent a diverse group of potential anti-cancer targets. The success of the first-in-class proteasome inhibitor bortezomib not only proved that the proteasome is a feasible and valuable anti-cancer target, but also inspired researchers to extensively explore other potential targets of this pathway. Areas covered This review provides a broad overview of the UPS and its role in supporting cancer development and progression, especially in aspects of p53 inactivation, p27 turnover and NF-κB activation. Also, efforts toward the development of small molecule inhibitors (SMIs) targeting different steps in this pathway for cancer treatment are reviewed and discussed. Expert opinion Whereas some of the targets in the UPS, such as the 20S pro-teasome, Nedd8 activating enzyme and HDM2, have been well-established and validated, there remains a large pool of candidates waiting to be investigated. Development of SMIs targeting the UPS has been largely facilitated by state-of-the-art technologies such as high-throughput screening and computer-assisted drug design, both of which require a better understanding of the targets of interest.

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

“…Indeed, it has been widely reported that ER stress is implicated in antitumoral effects of proteasome inhibitors. [34][35][36] Consistent with previous research, 21,22 the present study demonstrated that WA inhibited proteasome activity and accumulation of ubiquitinated proteins in PC cells. Subsequent investigations revealed that CHX attenuated WA-induced cell death, indicating that proteotoxicity is important for the effect of WA.…”

“…33 Thus, targeting of its pathway has emerged as effective antitumor approach. 34 Moreover, proteasome inhibition appears to prevent the clearance of misfolded proteins through the ERAD system, possibly triggering ER stress-mediated apoptosis. Indeed, it has been widely reported that ER stress is implicated in antitumoral effects of proteasome inhibitors.…”

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…Up-regulation of HDM2 by MAGE-A11 Increases E2F1 Transcriptional Activity That Is Inhibited by ARF-HDM2 E3 ubiquitin ligase is a proto-oncogene overexpressed in human cancers and a target for anticancer therapy (74,75). HDM2 stabilizes E2F1 and mediates ubiquitin-dependent degradation of p53 (54).…”

“…Stabilization and sequestration of MAGE-A11 and HDM2 by ARF may be involved in feedback control (79). Furthermore, HDM2 interaction with p300 is required for the proteasomal degradation of p53 (75). MAGE-A11 forms a strong complex with p300 in association with gene transcription (10) that inhibited the stabilization of HDM2 by MAGE-A11.…”

The Proteasome Subunit Rpn8 Interacts with the Small Nucleolar RNA Protein (snoRNP) Assembly Protein Pih1 and Mediates Its Ubiquitin-independent Degradation in Saccharomyces cerevisiae

“…However, we cannot rule out the possibility that ubiquitin-independent protein degradation via interaction with the Rpn8 C terminus might play a significant role in specific cell types or growth conditions. For example, most known proteins that undergo a ubiquitinindependent degradation pathway play critical regulatory roles, and many of them are oncoproteins or oncosuppressor proteins that are specifically degraded in fast dividing cancer cells (64,65). The high energy demand of cancer cells may partially limit the energy-consuming polyubiquitination pathway and promote ubiquitin-independent degradation of oncoproteins and/or oncosuppressor proteins.…”