The Proteasome Is a Molecular Target of Environmental Toxic Organotins

被引：35

作者：

Shi, Guoqing ^{[1
,2
,3
,4
]}

Chen, Di ^{[2
,3
]}

Zhai, Guangshu ^{[1
]}

Chen, Marina S. ^{[2
,3
]}

Cui, Qiuzhi Cindy ^{[2
,3
]}

Zhou, Qunfang ^{[1
]}

He, Bin ^{[1
]}

Dou, Q. Ping ^{[2
,3
]}

Jiang, Guibin ^{[1
]}

机构：

[1] Chinese Acad Sci, Ecoenvironm Sci Res Ctr, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China

[2] Barbara Ann Karmanos Canc Inst, Prevent Program, Detroit, MI USA

[3] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA

[4] Univ Sci & Technol, Sch Appl Sci, Beijing, Peoples R China

来源：

ENVIRONMENTAL HEALTH PERSPECTIVES | 2009年 / 117卷 / 03期

基金：

中国国家自然科学基金;

关键词：

cell death; molecular target; organotins; proteasome; proteasome inhibitors; TPT; CELL-DEATH; DIETARY FLAVONOIDS; CANCER-CELLS; APOPTOSIS; TRIBUTYLTIN; INHIBITORS; TRIPHENYLTIN; INVOLVEMENT; BAX; ACCUMULATION;

D O I：

10.1289/ehp.11865

中图分类号：

X [环境科学、安全科学];

学科分类号：

08 ; 0830 ;

摘要：

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.

引用

页码：379 / 386

页数：8

共 35 条

[1] Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts [J].