Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase
The ubiquitin–proteasome system (UPS) is indispensable to the protein quality control in eukaryotic cells. Due to the remarkable clinical success of using proteasome inhibitors for clinical treatment of multiple myeloma, it is anticipated that targeting the UPS upstream of the proteasome step be an effective strategy for cancer therapy. Deubiquitinases (DUB) are proteases that remove ubiquitin from target proteins and therefore regulate multiple cellular processes including some signaling pathways altered in cancer cells. Thus, targeting DUB is a promising strategy for cancer drug discovery. Previously, we have reported that metal complexes, such as copper and gold complexes, can disrupt the UPS via suppressing the activity of 19S proteasome-associated DUBs and/or of the 20S proteasomes, thereby inducing cancer cell death. In this study, we found that cadmium pyrithione (CdPT) treatment led to remarkable accumulation of ubiquitinated proteins in cultured cancer cells and primary leukemia cells. CdPT potently inhibited the activity of proteasomal DUBs (USP14 and UCHL5), but slightly inhibited 20S proteasome activity. The anti-cancer activity of CdPT was associated with triggering apoptosis via caspase activation. Moreover, treatment with CdPT inhibited proteasome function and repressed tumor growth in animal xenograft models. Our results show that cadmium-containing complex CdPT may function as a novel proteasomal DUB inhibitor and suggest appealing prospects for cancer treatment.
KeywordsCadmium Pyrithione Proteasome Deubiquitinase Tumor
This work was supported by the National High Technology Research and Development Program of China (2006AA02Z4B5), NSFC (81472762/H1609), MOE (20134423110002), Central Financial Grant of China (B16056001) (to J.L.), by Foundation for Young Innovative Talents of Guangdong Province (2016KQNCX136) and Guangdong Province Medical Science Research Foundation (A2017308) (to X.C.) and by US NIH R01 grants HL072166 and HL085629 (to X.W.).
- Anderson DJ, Le Moigne R, Djakovic S, Kumar B, Rice J, Wong S, Wang J, Yao B, Valle E, Kiss von Soly S, Madriaga A, Soriano F, Menon MK, Wu ZY, Kampmann M, Chen Y, Weissman JS, Aftab BT, Yakes FM, Shawver L, Zhou HJ, Wustrow D, Rolfe M (2015) Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28:653–665CrossRefPubMedPubMedCentralGoogle Scholar
- Chen X, Shi X, Zhao C, Li X, Lan X, Liu S, Huang H, Liu N, Liao S, Zang D, Song W, Liu Q, Carter BZ, Dou QP, Wang X, Liu J (2014) Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms. Oncotarget 5:9118–9132PubMedPubMedCentralGoogle Scholar
- Liu N, Li X, Huang H, Zhao C, Liao S, Yang C, Liu S, Song W, Lu X, Lan X, Chen X, Yi S, Xu L, Jiang L, Zhao C, Dong X, Zhou P, Li S, Wang S, Shi X, Dou PQ, Wang X, Liu J (2014a) Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth. Oncotarget 5:5453–5471PubMedPubMedCentralGoogle Scholar
- Liu N, Liu C, Li X, Liao S, Song W, Yang C, Zhao C, Huang H, Guan L, Zhang P, Liu S, Hua X, Chen X, Zhou P, Lan X, Yi S, Wang S, Wang X, Dou QP, Liu J (2014b) A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases. Sci Rep 4:5240CrossRefPubMedPubMedCentralGoogle Scholar
- Shi X, Chen X, Li X, Lan X, Zhao C, Liu S, Huang H, Liu N, Liao S, Song W, Zhou P, Wang S, Xu L, Wang X, Dou QP, Liu J (2014) Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation. Clin Cancer Res 20:151–163CrossRefPubMedGoogle Scholar
- Zhao C, Chen X, Zang D, Lan X, Liao S, Yang C, Zhang P, Wu J, Li X, Liu N, Liao Y, Huang H, Shi X, Jiang L, Liu X, He Z, Dou QP, Wang X, Liu J (2016a) A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy. Oncogene 35:5916–5927CrossRefPubMedPubMedCentralGoogle Scholar
- Zhao C, Chen X, Zang D, Lan X, Liao S, Yang C, Zhang P, Wu J, Li X, Liu N, Liao Y, Huang H, Shi X, Jiang L, Liu X, He Z, Wang X, Liu J (2016b) Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy. Biochem Pharmacol 116:22–38CrossRefPubMedPubMedCentralGoogle Scholar