Characterizing mechanisms of protein homeostasis, a process of balancing between
protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The
ubiquitin-
proteasome system (UPS) is a well-studied mechanism of
protein catabolism, which is responsible for eliminating misfolded, damaged, or aging
proteins, thereby maintaining quality and quantity of cellular
proteins. The UPS is composed of multiple components, including a series of
enzymes (E1, E2, E3, and
deubiquitinase [DUB]) and
26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including
cancer. Several
proteasome inhibitors, such as
bortezomib,
carfilzomib, and
ixazomib, are approved to treat patients with certain
cancers. However, their applications are limited by
side effects, drug resistance, and
drug-drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields.
Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as
20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of
metal-based anticancer drugs. In this review, we will summarize functions and applications of
copper complexes in a concise perspective, with a focus on connections between the UPS and
cancer.