title: Microcystin-LR induces anoikis resistance to the hepatocyte uptake transporter OATP1B3-expressing cell lines.
abstract: Microcystin-LR is a cyclic peptide released by several bloom-forming cyanobacteria. Understanding the mechanism of microcystin-LR toxicity is important, because of the both potencies of its acute cytotoxicity and tumor-promoting activity in hepatocytes of animals and humans. Recently, we have reported that the expression of human hepatocyte uptake transporter OATP1B3 was critical for the selective uptake of microcystin-LR into hepatocytes and for induction of its fatal cytotoxicity. In this study, we demonstrated a novel function of microcystin-LR which induced bipotential changes including anoikis resistance and cytoskeleton reorganization to OATP1B3-transfected HEK293 cells (HEK293-OATP1B3). After exposure to microcystin-LR, HEK293-OATP1B3 cells were divided to the floating cells and remaining adherent cells. After collection and reseeding the floating cells into a fresh flask, cells were confluently proliferated (HEK293-OATP1B3-FL) under the microcystin-LR-free condition. Both the proliferated HEK293-OATP1B3-FL and remaining adherent HEK293-OATP1B3-AD cells changed the character with down- and up-regulation of E-cadherin, respectively. Additionally, these cells acquired resistance to microcystin-LR. These results suggest that microcystin-LR could be associated with not only tumor promotion, but also epithelial-mesenchymal transition-mediated cancer metastasis. Furthermore, microcystin-LR might induce the cytoskeleton reorganization be accompanied epithelial-mesenchymal transition.
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
authors.affiliation: Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Takumi
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikema
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Mizoue
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hotta
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiozaki
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan. Electronic address: komatsu@fish.kagoshima-u.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D023102:Anoikis / Q000187:drug effects*; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000378:metabolism / Q000633:toxicity*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013997:Time Factors; D014162:Transfection
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002273:Carcinogens; D008387:Marine Toxins; D052998:Microcystins; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C057862:cyanoginosin LR
keywords: Anoikis resistance; Epithelial mesenchymal transition; Hepatotoxin; Microcystin-LR; OATP1B3