Hong Shin Yee, Yu Fa-Xing, Luo Yan, Hagen Thilo
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Cell Signal. 2016 May;28(5):377-383. doi: 10.1016/j.cellsig.2016.01.011. Epub 2016 Jan 28.
Oncogenic activation of the PI3K/Akt pathway is known to play an important role to promote glucose metabolism in cancer cells. However, the molecular mechanism through which the PI3K/Akt signalling pathway promotes glucose utilisation in cancer cells is still not well understood. It has recently been shown that the oncogenic activation of the PI3K/Akt/mTOR signalling in lung adenocarcinoma is important in promoting the localisation of glucose transporter 1 (GLUT1) at the plasma membrane. We thus hypothesised that the effect of constitutive activation of the PI3K/AKT signalling on glucose metabolism is mediated by thioredoxin interacting protein (TXNIP), a known regulator of the GLUT1 plasma membrane localisation. Consistent with previous studies, inhibition of the PI3K/Akt pathway decreased cellular glucose uptake. Furthermore, inhibition of PI3K/Akt signalling in non-small cell lung cancer (NSCLC) cell lines using clinically used tyrosine kinase inhibitors (TKIs) resulted in a decrease in GLUT1 membrane localisation. We also observed that inhibition of the PI3K/Akt pathway in various cell lines, including NSCLC cells, resulted in an increase in TXNIP expression. Importantly, knockdown of TXNIP using siRNA in the NSCLC cells promoted GLUT1 to be localised at the plasma membrane and reversed the effect of PI3K/Akt inhibitors. Together, our results suggest that the oncogenic activation of PI3K/Akt signalling promotes cellular glucose uptake, at least in part, through the regulation of TXNIP expression. This mechanism may contribute to the Warburg effect in cancer cells.
已知PI3K/Akt通路的致癌激活在促进癌细胞葡萄糖代谢中起重要作用。然而，PI3K/Akt信号通路促进癌细胞葡萄糖利用的分子机制仍未完全清楚。最近研究表明，肺腺癌中PI3K/Akt/mTOR信号的致癌激活在促进葡萄糖转运蛋白1（GLUT1）定位于质膜方面很重要。因此，我们推测PI3K/AKT信号的组成性激活对葡萄糖代谢的影响是由硫氧还蛋白相互作用蛋白（TXNIP）介导的，TXNIP是GLUT1质膜定位的已知调节因子。与先前研究一致，抑制PI3K/Akt通路可降低细胞葡萄糖摄取。此外，使用临床常用的酪氨酸激酶抑制剂（TKIs）抑制非小细胞肺癌（NSCLC）细胞系中的PI3K/Akt信号，导致GLUT1膜定位减少。我们还观察到，在包括NSCLC细胞在内的各种细胞系中抑制PI3K/Akt通路会导致TXNIP表达增加。重要的是，在NSCLC细胞中使用siRNA敲低TXNIP可促进GLUT1定位于质膜，并逆转PI3K/Akt抑制剂的作用。总之，我们的结果表明，PI3K/Akt信号的致癌激活至少部分通过调节TXNIP表达来促进细胞葡萄糖摄取。这种机制可能有助于癌细胞的瓦伯格效应。
