title: AMP-activated protein kinase-mediated glucose transport as a novel target of tributyltin in human embryonic carcinoma cells.
abstract: Organotin compounds such as tributyltin (TBT) are known to cause various forms of cytotoxicity, including developmental toxicity and neurotoxicity. However, the molecular target of the toxicity induced by nanomolar levels of TBT has not been identified. In the present study, we found that exposure to 100 nM TBT induced growth arrest in human pluripotent embryonic carcinoma cell line NT2/D1. Since glucose provides metabolic energy, we focused on the glycolytic system. We found that exposure to TBT reduced the levels of both glucose-6-phosphate and fructose-6-phosphate. To investigate the effect of TBT exposure on glycolysis, we examined glucose transporter (GLUT) activity. TBT exposure inhibited glucose uptake via a decrease in the level of cell surface-bound GLUT1. Furthermore, we examined the effect of AMP-activated protein kinase (AMPK), which is known to regulate glucose transport by facilitating GLUT translocation. Treatment with the potent AMPK activator, AICAR, restored the TBT-induced reduction in cell surface-bound GLUT1 and glucose uptake. In conclusion, these results suggest that exposure to nanomolar levels of TBT causes growth arrest by targeting glycolytic systems in human embryonic carcinoma cells. Thus, understanding the energy metabolism may provide new insights into the mechanisms of metal-induced cytotoxicity.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku 158-8501, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.forename: Yaichiro
authors.initials: Y
authors.lastname: Kotake
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054278:Embryonal Carcinoma Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D014220:Trialkyltin Compounds; C011559:tributyltin; D055372:AMP-Activated Protein Kinases; D005947:Glucose