The Proteasome Is a Molecular Target of Environmental Toxic Organotins

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.

[1]  W. Mundy,et al.  Apoptosis of cerebellar granule cells induced by organotin compounds found in drinking water: involvement of MAP kinases. , 2006, Neurotoxicology.

[2]  W. Guida,et al.  Docking studies and model development of tea polyphenol proteasome inhibitors: Applications to rational drug design , 2003, Proteins.

[3]  R. Huber,et al.  Structure of 20S proteasome from yeast at 2.4Å resolution , 1997, Nature.

[4]  S. Orrenius,et al.  Caspase involvement in the induction of apoptosis by the environmental toxicants tributyltin and triphenyltin. , 1999, Toxicology and applied pharmacology.

[5]  M. Larsen,et al.  Accumulation of organotin compounds and mercury in harbour porpoises (Phocoena phocoena) from the Danish waters and West Greenland. , 2005, The Science of the total environment.

[6]  William H. Beers,et al.  The Scripps Research Institute , 1996, Current Biology.

[7]  H. Harino,et al.  Accumulation of Organotin Compounds in Tissues and Organs of Stranded Whales Along the Coasts of Thailand , 2007, Archives of environmental contamination and toxicology.

[8]  M. Lekka,et al.  Molecular mechanism of haemolysis induced by triphenyltin chloride , 2002 .

[9]  K. Fent,et al.  Ecotoxicology of organotin compounds. , 1996, Critical reviews in toxicology.

[10]  Di Chen,et al.  Structure-proteasome-inhibitory activity relationships of dietary flavonoids in human cancer cells. , 2007, Frontiers in bioscience : a journal and virtual library.

[11]  D. Kime,et al.  Early life exposure to environmental levels of the aromatase inhibitor tributyltin causes masculinisation and irreversible sperm damage in zebrafish (Danio rerio). , 2003, Aquatic toxicology.

[12]  Aaron Ciechanover,et al.  The ubiquitin–proteasome pathway: on protein death and cell life , 1998, The EMBO journal.

[13]  Lihong Xu,et al.  Apoptotic related biochemical changes in human amnion cells induced by tributyltin. , 2007, Toxicology.

[14]  P. J. Smith,et al.  Selective decline in imposex levels in the dogwhelk Lepsiella scobina following a ban on the use of TBT antifoulants in New Zealand , 1996 .

[15]  S. Ohta,et al.  Glutamate excitotoxicity is involved in cell death caused by tributyltin in cultured rat cortical neurons. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[16]  Q. Dou,et al.  Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Q. Dou,et al.  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 , 1998, Cell Death and Differentiation.

[18]  J. Tobin,et al.  Role of speciation in organotin toxicity to the yeast Candida maltosa. , 2004, Environmental science & technology.

[19]  W. Seinen,et al.  Biological activity of organotin compounds--an overview. , 1987, Environmental research.

[20]  V. Andrisano,et al.  Potential of Pyrazolooxadiazinone Derivatives as Serine Protease Inhibitors , 2001, Journal of enzyme inhibition.

[21]  Di Chen,et al.  Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. , 2005, Biochemical pharmacology.

[22]  G. Gao,et al.  N‐terminal cleavage of Bax by calpain generates a potent proapoptotic 18‐kDa fragment that promotes Bcl‐2‐independent cytochrome C release and apoptotic cell death , 2000, Journal of cellular biochemistry.

[23]  J. Giesy,et al.  Occurrence of butyltin compounds in human blood , 1999 .

[24]  U. Lopes,et al.  p53-dependent Induction of Apoptosis by Proteasome Inhibitors* , 1997, The Journal of Biological Chemistry.

[25]  E. Corsini,et al.  NF-κB Activation by Triphenyltin Triggers Apoptosis in HL-60 Cells , 1996 .

[26]  E. Newcomb,et al.  Cleavage of Bax enhances its cell death function. , 2000, Experimental cell research.

[27]  A. Goldberg.  Functions of the proteasome: the lysis at the end of the tunnel. , 1995, Science.

[28]  C. Mendelson,et al.  O2 Enhancement of Human Trophoblast Differentiation and hCYP19 (Aromatase) Gene Expression Are Mediated by Proteasomal Degradation of USF1 and USF2 , 2005, Molecular and Cellular Biology.

[29]  P. E. Gibbs,et al.  The effect of tributyltin upon steroid titres in the female dogwhelk, Nucella lapillus, and the development of imposex , 1991 .

[30]  R F Standaert,et al.  Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin , 1995, Science.

[31]  Bruce Blumberg,et al.  Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. , 2006, Molecular endocrinology.

[32]  D. Boothman,et al.  Activation of a cysteine protease in MCF-7 and T47D breast cancer cells during beta-lapachone-mediated apoptosis. , 2000, Experimental cell research.

[33]  Q. Dou,et al.  Proteasome inhibitors as potential novel anticancer agents. , 1999, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.