Targeting the ubiquitin‐proteasome system for cancer therapy

Abstract

The ubiquitin-proteasome system plays a critical role in controlling the level, activity and location of various cellular proteins. Significant progress has been made in investigating the molecular mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying ubiquitin protein ligases, the primary specificity-determining enzymes. Therefore, it is now possible to target specific molecules involved in ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all, cancer cells. This is manifested by destabilization of tumor suppressors, such as p53, and overexpression of oncogenes such as c-Myc and c-Jun. In addition to the development and clinical validation of proteasome inhibitor, bortezomib, in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes. With the help of structural studies, rational design and chemical synthesis, it is conceivable that we will be able to use 'druggable' inhibitors of the ubiquitin system to evaluate their effects in animal tumor models in the not-so-distant future. (Cancer Sci 2009; 100: 24-28) Ubiquitin system U biquitination is catalyzed by the sequential action of E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme) and E3 (ubiquitin protein ligase), which leads to the conjugation of ubiquitin to the ε-amino group of a lysine residue in target proteins (Fig. 1).(1) Under certain circumstances, ubiquitin can also be conjugated to the N-terminal or even non-lysine residues of proteins.(2,3) Interestingly, the formation of the polyubiquitin chain on certain proteins requires an additional factor (E4), (4) whereas monoubiquitination of protein that contains a ubiquitin-binding domain may occur in the absence of E3. (5) Additionally, there is a family of small ubiquitin-like modifiers (Ubl), including SUMO, Nedd8, FAT10 and ISG15. They can be conjugated to lysine residues of specific target proteins through mechanisms parallel to but distinct from that of ubiquitin. (6) While SUMO can be conjugated to a variety of substrate proteins, other Ubl appear to have a limited number of targets. Besides affecting many cellular activities directly, these modifications also regulate ubiquitination at multiple levels. (7,8) Intriguingly, RING protein Hdm2 can function as ligase for both ubiquitin and Nedd8.(9) RING protein Topors can act as an E3 for both ubiquitin and SUMO. (10) Although it is generally believed that there is only one E1 (UBE1) in human cells, recent studies have shown that both UBE1L2 and Uba6 can activate ubiquitin.(11-13) Because they only transfer ubiquitin to particular E2s, it is likely that UBE1L2 and Uba6 may regulate a subset of ubiquitinations or modulate ubiquitination at specific organs. There are more than 40 putative E2s in mammalian cells, and each...

Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

“…Inhibition of the proteasome generates a high degree of proteotoxic stress and is known to induce both the HSR and the UPR (Fribley et al 2004;Neznanov et al 2011). Proteasome inhibitors, such as Velcade®, are currently being clinically evaluated in combination with conventional chemotherapy in a number of cancer types to determine therapeutic efficacy (Yang et al 2009). The rationale behind this approach is to generate proteotoxic stress levels that exceed the buffering capacity of the cancer cell stress pathways, generating 'stress overload' and inducing cancer cell death.…”

Ubiquitination and Downregulation of BRCA1 by Ubiquitin-Conjugating Enzyme E2T Overexpression in Human Breast Cancer Cells

“…Therefore, several cancer-therapeutic inhibitors targeting the ubiquitin-proteasome system have been developed: PYR-41 (a cell permeable inhibitor of the ubiquitin E1, UBE1), HLI98 (a small compound inhibitor which block Hdm2-mediated p53 ubiqutination), and bortezomib (a dipeptide boronate inhibitor of 26S proteasome; ref. 33). However, because PYR-41 or bortezomib are distinct from target-specific inhibition, these inhibitors are thought to block whole cellular system mediated by ubiquitin pathways (33,34).…”

“…However, because PYR-41 or bortezomib are distinct from target-specific inhibition, these inhibitors are thought to block whole cellular system mediated by ubiquitin pathways (33,34). In addition, the development of E3 ligase inhibitors such as HLI98 has been challenged by structural similarities among E3 enzymes that are present in >600 proteins in human cells, consequently resulting in off target effect (33).…”

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

“…However, we believe that this dual specificity may be exploited to target at the same time two relevant pathways for cancer onset and progression (69,70). Interestingly, the association of γ-secretase inhibitors with chemotherapy has been proposed very recently as a novel approach for the treatment of metastatic colon cancer (71), whereas the use of proteasome inhibitors into the clinic dates back of a decade and now is part of the standard treatment of some hematologic malignancies (72).…”