Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
Department of Chemistry, Yonsei University, 03722 Seoul, Korea.
Nat Chem. 2017 Jul;9(7):667-675. doi: 10.1038/nchem.2706. Epub 2017 Jan 30.
Perturbations in cellular chloride concentrations can affect cellular pH and autophagy and lead to the onset of apoptosis. With this in mind, synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here, we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in lysosomal pH, which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.
细胞氯离子浓度的紊乱会影响细胞 pH 值和自噬，从而导致细胞凋亡。有鉴于此，人们已经使用合成离子转运体来扰乱细胞离子动态平衡，从而诱导细胞死亡；然而，目前尚不清楚合成离子转运体是否也可用于破坏自噬。在这里，我们表明基于 squaramide 的离子转运体增强了脂质体模型中氯离子阴离子的转运，并促进了氯化钠流入细胞质。证明 squaramide 的脂质体和细胞转运活性与细胞死亡活性相关，这归因于半胱天冬酶依赖性细胞凋亡。一种离子转运体还显示会引起溶酶体 pH 值的其他变化，从而导致溶酶体酶活性受损和自噬过程中断。这种中断与离子转运体引发的细胞凋亡无关。这项研究首次提供了实验证据，证明合成离子转运体可以破坏自噬并诱导细胞凋亡。
