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Cadmium pyrithione suppresses tumor growth in vitro and in vivo through inhibition of proteasomal deubiquitinase
Authors:Xin Chen  Jinjie Wu  Qianqian Yang  Xiaolan Zhang  Peiquan Zhang  Siyan Liao  Zhimin He  Xuejun Wang  Chong Zhao  Jinbao Liu
Institution:1.Protein Modification and Degradation Lab, School of Basic Medical Sciences,Affiliated Tumor Hospital of Guangzhou Medical University,Guangzhou,China;2.Department of Pharmacy, Tongji Hospital, Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China;3.Cancer Hospital and Cancer Research Institute,Guangzhou Medical University,Guangzhou,China;4.Division of Basic Biomedical Sciences,Sanford School of Medicine of the University of South Dakota,Vermillion,USA;5.Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital,Guangzhou Medical University,Guangzhou,China
Abstract: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.
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