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.

NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells

“…Therefore, the reduction of ATP caused by TBT treatment might be involved in neuronal differentiation. Moreover, TBT has been reported to cause cell growth arrest in NT2/D1 cells20. Because cell growth is generally reduced during differentiation, we examined whether TBT affects the neuronal differentiation process in NT2/D1 cells.…”

“…Thus, the mechanism of nM concentrations of TBT has not been elucidated at a non-genomic level. In a previous study, we reported that treatment with 100 nM TBT resulted in growth arrest by targeting the glycolytic systems of the human embryonic carcinoma cell line NT2/D120. Therefore, we raised the possibility that nM concentrations of TBT may target other non-genomic pathways which are involved in energy metabolism.…”

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

“…We have previously found that 100 nM TBT induced growth arrest in NT2/D1 cells (Yamada et al, 2013). Here we investigated whether TBT affects cell cycle progression.…”

“…We have previously reported that nanomolar levels of TBT induce growth arrest of neuronal precursor NT2/D1 cells as a model of neurodevelopmental stage (Yamada et al, 2013). We found that TBT causes growth arrest via mitochondrial NAD + -dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the irreversible conversion of isocitrate to α-ketoglutarate in the tricarboxylic acid (TCA) cycle .…”

Cell-type-specific and differentiation-status-dependent variations in cytotoxicity of tributyltin in cultured rat cerebral neurons and astrocytes

“…Although comprehensive molecular mechanisms of TBT toxicity are largely unknown, these recent studies and others have proposed various molecular targets of TBT. Among them, peroxisome proliferator-activated receptor (PPAR) γ and retinoid X receptor complex (Hiromori et al, 2014), AMP-activated protein kinase (Yamada et al, 2013) are especially important when considering adverse effects of TBT on the CNS because neurons and astrocytes in the CNS abundantly express and effectively utilize these proteins (Gatson et al, 2011;Taib et al, 2013;Aleshin et al, 2009;Ronnett et al, 2009). On the other hand, TBT was also known as a potent inhibitor of F-ATP synthase (von Ballmoos et al, 2004;Nesci et al, 2014), which would be also important because inhibition of cellular ATP synthesis results in cell death immediately.…”