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: Hiroyuki Takano, Shota Takumi, Satoshi Ikema, Nozomi Mizoue, Yuki Hotta, Kazuhiro Shiozaki, Yasumasa Sugiyama, Tatsuhiko Furukawa, Masaharu Komatsu
• Journal: Toxicology (Toxicology) Vol. 326 Pg. 53-61 (Dec 04 2014) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 25456266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• Carcinogens
• Marine Toxins
• Microcystins
• Organic Anion Transporters, Sodium-Independent
• SLCO1B3 protein, human
• Solute Carrier Organic Anion Transporter Family Member 1B3
• cyanoginosin LR

Topics

• Anoikis (drug effects)
• Antigens, CD
• Cadherins (metabolism)
• Carcinogens (metabolism, toxicity)
• Cell Adhesion (drug effects)
• Cell Survival (drug effects)
• Cytoskeleton (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance
• Epithelial-Mesenchymal Transition (drug effects)
• HEK293 Cells
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Marine Toxins
• Microcystins (metabolism, toxicity)
• Organic Anion Transporters, Sodium-Independent (genetics, metabolism)
• Solute Carrier Organic Anion Transporter Family Member 1B3
• Time Factors
• Transfection