AUTHOR=Chen Xin , Dou Q. Ping , Liu Jinbao , Tang Daolin 

TITLE=Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.649151

DOI=10.3389/fmolb.2021.649151

ISSN=2296-889X

ABSTRACT=Characterizing the mechanisms of protein homeostasis, a process of balancing between
protein synthesis and protein degradation, is very important for understanding the potential
causes of human diseases. The ubiquitin proteasome system (UPS) is the well-studied
mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or
aging proteins, thereby maintaining the 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).
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 the 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 the core component
of the UPS machinery, such as 20S proteasome, 19S proteasomal DUBs, and NPLOC4/NPL4
complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we
will summarize the functions and applications of copper complexes in a concise perspective,
with a focus on the connection between the UPS and cancer.