AMP-activated protein kinase-mediated glucose transport as a novel target of tributyltin in human embryonic carcinoma cells.
AMP-activated protein kinase-mediated glucose transport as a novel target of tributyltin in human embryonic carcinoma cells.
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DOI：
10.1039/c3mt20268b
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Shigeru Yamada;Y. Kotake;Y. Sekino;Y. Kanda
中科院分区：
文献类型：
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作者：
Shigeru Yamada;Y. Kotake;Y. Sekino;Y. Kanda
已知有机锡化合物如三丁基锡（TBT）会引起各种形式的细胞毒性，包括发育毒性和神经毒性。然而，尚未确定纳摩尔三丁基锡化合物引起毒性的分子靶点。在本研究中，我们发现，暴露于100 nM TBT诱导生长停滞在人多能胚胎癌细胞系NT 2/D1。由于葡萄糖提供代谢能量，我们专注于糖酵解系统。我们发现，暴露于TBT降低了葡萄糖-6-磷酸和果糖-6-磷酸的水平。为了研究TBT暴露对糖酵解的影响，我们检测了葡萄糖转运蛋白（GLUT）的活性。接触三丁基锡化合物可通过降低细胞表面结合的GLUT 1水平来抑制葡萄糖摄取。此外，我们研究了AMP激活的蛋白激酶（AMPK）的作用，已知AMPK通过促进GLUT易位来调节葡萄糖转运。用有效的AMPK激活剂AICAR治疗，恢复了TBT诱导的细胞表面结合GLUT 1和葡萄糖摄取的减少。总之，这些结果表明，暴露于纳摩尔水平的三丁基锡化合物导致生长停滞的目标糖酵解系统在人类胚胎癌细胞。因此，了解能量代谢可能提供新的见解金属诱导的细胞毒性的机制。
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.