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.
keywords
TRANSMEMBRANE ANION TRANSPORTERS; SMALL-MOLECULE; CYTOCHROME-C; DEATH; ATPASE; ACIDIFICATION; TRAFFICKING; DISSECTION; LYSOSOMES; MEMBRANES
subject category
Chemistry
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
our authors
Igor Oliveira Marques
Junior Researcher
Vítor Félix
Associate Professor with AggregationProjects
CICECO - Aveiro Institute of Materials (UID/CTM/50011/2013)
Solucao de Engenharia Microestrutural para Aumentar o Transporte Ionico Interfacial (MERIT)
acknowledgements
This study was supported financially by the National Creative Research Initiative (grant no. 2010-0018272 to I.S.) and Basic Science Research programmes (grant no. NRF-2012R1A1A1040142 to W.N.) in Korea. P.A.G. acknowledges the EPSRC for postdoctoral fellowships (EP/J009687/1 to N.B. and E.N.W.H.) and the Royal Society and the Wolfson Foundation for a Research Merit Award. The work in Austin was supported by the National Institutes of Health (grant no. GM103790 to J.L.S.). The theoretical studies were supported by projects P2020-PTDC/QEQ-SUP/4283/2014, CICECO - Aveiro Institute of Materials (UID/CTM/50011/2013) and iBiMED - Institute of Biomedicine (UID/BIM/04501/2013), financed by National Funds through the FCT/MEC and co-financed by QREN-FEDER through COMPETE under the PT2020 Partnership Agreement. I.M. acknowledges the FCT for PhD scholarship SFRH/BD/87520/2012. The authors thank H.J. Clarke for resynthesizing compound 5.