A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations

authors	Busschaert, N; Park, SH; Baek, KH; Choi, YP; Park, J; Howe, ENW; Hiscock, JR; Karagiannidis, LE; Marques, I; Felix, V; Namkung, W; Sessler, JL; Gale, PA; Shin, I
nationality	International
journal	NATURE CHEMISTRY
keywords	TRANSMEMBRANE ANION TRANSPORTERS; SMALL-MOLECULE; CYTOCHROME-C; DEATH; ATPASE; ACIDIFICATION; TRAFFICKING; DISSECTION; LYSOSOMES; MEMBRANES
abstract	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.
publisher	NATURE PUBLISHING GROUP
issn	1755-4330
year published	2017
volume	9
issue	7
beginning page	667
ending page	675
digital object identifier (doi)	10.1038/NCHEM.2706
web of science category	Chemistry, Multidisciplinary
subject category	Chemistry
unique article identifier	WOS:000404056800014