A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases

Abstract

The successful development of bortezomib-based therapy for treatment of multiple myeloma has established proteasome inhibition as an effective therapeutic strategy, and both 20S proteasome peptidases and 19S deubiquitinases (DUBs) are becoming attractive targets of cancer therapy. It has been reported that metal complexes, such as copper complexes, inhibit tumor proteasome. However, the involved mechanism of action has not been fully characterized. Here we report that (i) copper pyrithione (CuPT), an alternative to tributyltin for antifouling paint biocides, inhibits the ubiquitin-proteasome system (UPS) via targeting both 19S proteasome-specific DUBs and 20S proteolytic peptidases with a mechanism distinct from that of the FDA-approved proteasome inhibitor bortezomib; (ii) CuPT potently inhibits proteasome-specific UCHL5 and USP14 activities; (iii) CuPT inhibits tumor growth in vivo and induces cytotoxicity in vitro and ex vivo. This study uncovers a novel class of dual inhibitors of DUBs and proteasome and suggests a potential clinical strategy for cancer therapy.

Disassembly of Lys11 and Mixed Linkage Polyubiquitin Conjugates Provides Insights into Function of Proteasomal Deubiquitinases Rpn11 and Ubp6

“…Inhibition of USP14 increased the turnover of oxidized and damaged proteins by the proteasome (60). In addition, the therapeutic importance of inhibiting USP14 and UCHL5 have been demonstrated for controlling progression of acute myeloid leukemia (63,64) or tumor growth (93). Although its roles in cell viability, life span, and cancers (94 -96) make it a promising drug target (62), there are currently no specific inhibitors for the Rpn11 metalloprotease.…”

“…Although its roles in cell viability, life span, and cancers (94 -96) make it a promising drug target (62), there are currently no specific inhibitors for the Rpn11 metalloprotease. An ability to study individual proteasome-associated DUBs in isolation should facilitate intensive ongoing drug discovery efforts (61,63,93,(97)(98)(99) relative to the dynamic, ATP-dependent, multisubunit proteasome complex.…”

Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells

“…Copper ions or copper-containing agents have been largely investigated for their ability to inhibit UPS function in cancer cells [8][9][10]. Copper complex CuPT can induces cancer cell death through targeting both 19S proteasomal DUBs and 20S proteasome peptidases [10], which is distinct from the clinical used proteasome inhibitor bortezomib.…”

“…Several copper-binding agents have been investigated for their ability to bind copper and impair UPS function in malignant cells [8][9][10]. We have previously demonstrated that copper pyrithione (CuPT), a copper complex used as antifouling paint biocides, induces cancer cell death by targeting both 19S proteasomal DUBs and 20S proteasome peptidases [10].…”

“…We have previously demonstrated that copper pyrithione (CuPT), a copper complex used as antifouling paint biocides, induces cancer cell death by targeting both 19S proteasomal DUBs and 20S proteasome peptidases [10]. Although copper complexes exhibit strong anticancer activities, the undesired side effects may prevent them from entering clinical trials [11].…”