| The Proteasome Is a Molecular Target of Environmental Toxic Organotins Guoqing Shi,1,2,3,* Di Chen,2,* Guangshu Zhai,1 Marina S. Chen,2 Qiuzhi Cindy Cui,2 Qunfang Zhou,1 Bin He,1 Q. Ping Dou,2,** and Guibin Jiang1,** 1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, People's Republic of China; 2Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA; 3School of Applied Science, University of Science and Technology Beijing, Beijing, People's Republic of China Abstract
Background: Because of the vital importance of the proteasome pathway, chemicals affecting proteasome activity could disrupt essential cellular processes. Although the toxicity of organotins to both invertebrates and vertebrates is well known, the essential cellular target of organotins has not been well identified. We hypothesize that the proteasome is a molecular target of environmental toxic organotins. Objectives: Our goal was to test the above hypothesis by investigating whether organotins could inhibit the activity of purified and cellular proteasomes and, if so, the involved molecular mechanisms and downstream events. Results: We found that some toxic organotins [e.g., triphenyltin (TPT) ] can potently and preferentially inhibit the chymotrypsin-like activity of purified 20S proteasomes and human breast cancer cellular 26S proteasomes. Direct binding of tin atoms to cellular proteasomes is responsible for the observed irreversible inhibition. Inhibition of cellular proteasomes by TPT in several human cell lines results in the accumulation of ubiquitinated proteins and natural proteasome target proteins, accompanied by induction of cell death. Conclusions: The proteasome is one of the molecular targets of environmental toxic organotins in human cells, and proteasome inhibition by organotins contributes to their cellular toxicity. Key words: cell death, molecular target, organotins, proteasome, proteasome inhibitors, TPT. Environ Health Perspect 117:379–386 (2009) . doi:10.1289/ehp.11865 available via http://dx.doi.org/ [Online 23 October 2008]
Address correspondence to G. Jiang, Research Center for Eco-Environmental Sciences, P.O. Box 2871, Beijing, 100085, China. Telephone: 86-10-6284-9179. Fax: 86-10-6284-9179. E-mail: gbjiang@rcees.ac.cn * These authors contributed equally to this work. ** These authors contributed equally to this work. This work was supported by the State High Tech Development (2006AA06Z424) and National Natural Science Foundation of China (20621703, 20897010) to G.J. ; Department of Defense Breast Cancer Research Program Awards (W81XWH-04-1-0688 and DAMD17-03-1-0175) to Q.P.D. ; and a China state scholarship to G.S. The authors declare they have no competing financial interests. Received 26 June 2008 ; accepted 23 October 2008.
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