title: Lentivirus-mediated silencing of I2PP2A through RNA interference attenuates trichloroethylene-induced cytotoxicity in human hepatic L-02 cells.
abstract: Trichloroethylene (TCE) is a common chemical pollutant that exists in air, soil, and drinking water. TCE exposure is known to cause severe hepatotoxicity; however, the mechanisms underlying TCE hepatotoxicity remain poorly understood. In a previous proteomics study, we found that TCE exposure up-regulated the expression of the inhibitor 2 of protein phosphatase 2A (I2PP2A), a potent and specific endogenous inhibitor of protein phosphatase (PP) 2A, in human hepatic L-02 cells. Here, we employed lentivirus-mediated RNA interference (RNAi) to knock down I2PP2A expression in L-02 cells and explored the potential role of I2PP2A in TCE-induced cytotoxicity. We found that TCE treatment of L-02 cells causes decreased cell viability, increased apoptosis and elevated I2PP2A mRNA and protein levels. TCE-treated L-02 cells were also found to have significantly reduced PP2A activity. Lentivirus-mediated I2PP2A knockdown partially prevented the decrease in viability and increased apoptosis induced by TCE treatment. Knockdown of I2PP2A in TCE-treated L-02 cells also suppressed the inhibition of PP2A activity and prevented caspase-3 activation. These data for the first time demonstrate that the up-regulation of I2PP2A could mediate, at least in part, TCE-induced liver cell toxicity through the inhibition of PP2A activity and caspase-3-mediated pathway, and suggest that I2PP2A may play a crucial role in mediating TCE hepatotoxicity.
authors.affiliation: Key Laboratory of Modern Toxicology of Shenzhen, Medical Key Laboratory of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China.
authors.forename: Xifei
authors.initials: X
authors.lastname: Yang
authors.forename: Yingzhi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Wen-Xu
authors.initials: WX
authors.lastname: Hong
authors.forename: Desheng
authors.initials: D
authors.lastname: Wu
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Huang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Lingqing
authors.initials: L
authors.lastname: Yang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Yuan
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D056488:Histone Chaperones / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D056488:Histone Chaperones; D034741:RNA, Small Interfering; C513473:SET protein, human; D014157:Transcription Factors; D014241:Trichloroethylene