title: MCLR-induced PP2A inhibition and subsequent Rac1 inactivation and hyperphosphorylation of cytoskeleton-associated proteins are involved in cytoskeleton rearrangement in SMMC-7721 human liver cancer cell line.
abstract: Cyanobacteria-derived toxin microcystin-LR (MCLR) has been widely investigated in its effects on normal cells, there is little information concerning its effects on cancer cells. In the present study, the SMMC-7721 human liver cancer cell line treated with MCLR was used to investigate the change of PP2A, cytoskeleton rearrangement, phosphorylation levels of PP2A substrates that related with cytoskeleton stability and explored underlying mechanisms. Here, we confirmed that MCLR entered into SMMC-7721 cells, bound to PP2A/C subunit and inhibited the activity of PP2A. The upregulation of phosphorylation of the PP2A/C subunit and PP2A regulation protein α4, as well as the change in the association of PP2A/C with α4, were responsible for the decrease in PP2A activity. Another novel finding is that the rearrangement of filamentous actin and microtubules led by MCLR may attribute to the increased phosphorylation of HSP27, VASP and cofilin due to PP2A inhibition. As a result of weakened interactions with PP2A and alterations in its subcellular localization, Rac1 may contribute to the cytoskeletal rearrangement induced by MCLR in SMMC-7721 cells. The current paper presents the first report demonstrating the characteristic of PP2A in MCLR exposed cancer cells, which were more susceptible to MCLR compared with the normal cell lines we previously found, which may be owing to the absence of some type of compensatory mechanisms. The hyperphosphorylation of cytoskeleton-associated proteins and Rac1 inactivation which were induced by inhibition of PP2A are shown to be involved in cytoskeleton rearrangement.
authors.affiliation: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Zhejiang Center for Disease Control and Prevention, Hangzhou 310051, China.
authors.forename: Mingluan
authors.initials: M
authors.lastname: Xing
authors.affiliation: Department of Biosystem Engineering, College of Biosystem Engineering and Food Science, Zhejiang University, Hangzhou 310058, China. Electronic address: zlguo@zju.edu.cn.
authors.forename: Zonglou
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: xulihong@zju.edu.cn.
authors.forename: Lihong
authors.initials: L
authors.lastname: Xu
mesh_terms: D001427:Bacterial Toxins / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D000087522:Cyanobacteria Toxins; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008387:Marine Toxins / Q000633:toxicity*; D052998:Microcystins / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D000087522:Cyanobacteria Toxins; D003598:Cytoskeletal Proteins; D004785:Environmental Pollutants; D008387:Marine Toxins; D052998:Microcystins; C078588:microcystin; D054648:Protein Phosphatase 2; D020830:rac1 GTP-Binding Protein
keywords: Cofilin; HSP27; Microcystin; PP2A; Rac1; VASP