Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

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  • Asanagi Miki
    Division of Pharmacology, National Institute of Health Sciences Faculty of Engineering, Department of Materials Science and Engineering, Yokohama National University
  • Yamada Shigeru
    Division of Pharmacology, National Institute of Health Sciences
  • Hirata Naoya
    Division of Pharmacology, National Institute of Health Sciences
  • Itagaki Hiroshi
    Faculty of Engineering, Department of Materials Science and Engineering, Yokohama National University
  • Kotake Yaichiro
    Department of Xenobiotic Metabolism and Molecular Toxicology, Graduate School of Biomedical and Health Sciences, Hiroshima University
  • Sekino Yuko
    Division of Pharmacology, National Institute of Health Sciences
  • Kanda Yasunari
    Division of Pharmacology, National Institute of Health Sciences

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  • Tributyltin induces G2/M cell cycle arrest via NAD⁺-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

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Abstract

Organotin compounds, such as tributyltin (TBT), are well-known endocrine-disrupting chemicals (EDCs). We have recently reported that TBT induces growth arrest in the human embryonic carcinoma cell line NT2/D1 at nanomolar levels by inhibiting NAD+-dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the irreversible conversion of isocitrate to α-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear. In the present study, we examined whether TBT at nanomolar levels affects cell cycle progression in NT2/D1 cells. Propidium iodide staining revealed that TBT reduced the ratio of cells in the G1 phase and increased the ratio of cells in the G2/M phase. TBT also reduced cell division cycle 25C (cdc25C) and cyclin B1, which are key regulators of G2/M progression. Furthermore, apigenin, an inhibitor of NAD-IDH, mimicked the effects of TBT. The G2/M arrest induced by TBT was abolished by NAD-IDHα knockdown. Treatment with a cell-permeable α-ketoglutarate analogue recovered the effect of TBT, suggesting the involvement of NAD-IDH. Taken together, our data suggest that TBT at nanomolar levels induced G2/M cell cycle arrest via NAD-IDH in NT2/D1 cells. Thus, cell cycle analysis in embryonic cells could be used to assess cytotoxicity associated with nanomolar level exposure of EDCs.

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