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

A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations
A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations
Perturbations in cellular chloride concentrations can affect cellular pH, 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 the 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.
1755-4330
667–675
Busschaert, Nathalie
bf307f09-0a86-4a03-afd8-4b0a59a8f72b
Park, Seong-Hyun
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Baek, Kyung-Hwa
3a576be8-7dac-49a1-9441-9ff8e1dc3e48
Choi, Soon Pyo
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Park, Jinhong
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Howe, Ethan
be05ae9a-02e0-443b-97b2-d65cc387af40
Hiscock, Jennifer
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Karagiannidis, Louise
fd53b5b4-0fc2-41ff-a665-e3185e8c8589
Marques, Igor
97cbc26e-6d94-43e6-a934-1d69dad8de06
Felix, Vitor
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Namkung, Wan
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Sessler, Jonathan
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Gale, Phil
c840b7e9-6847-4843-91af-fa0f8563d943
Shin, Injae
486117e1-e1ed-4ef6-95c2-2f8dd45f1c23
Busschaert, Nathalie
bf307f09-0a86-4a03-afd8-4b0a59a8f72b
Park, Seong-Hyun
f2891741-d905-49bb-ba4f-8c0b66e3474d
Baek, Kyung-Hwa
3a576be8-7dac-49a1-9441-9ff8e1dc3e48
Choi, Soon Pyo
9903d883-1045-4828-af37-8dc2fd54bc39
Park, Jinhong
45d2efaf-4e0f-4193-b732-43c77d68d193
Howe, Ethan
be05ae9a-02e0-443b-97b2-d65cc387af40
Hiscock, Jennifer
99a8a34c-a869-48e2-b713-1e69e4741032
Karagiannidis, Louise
fd53b5b4-0fc2-41ff-a665-e3185e8c8589
Marques, Igor
97cbc26e-6d94-43e6-a934-1d69dad8de06
Felix, Vitor
2d812f44-51b9-4359-9f8b-0e644342c0fe
Namkung, Wan
a20dc0ae-2647-4ee7-aee6-8e62e5a37ca2
Sessler, Jonathan
b4042afa-b7cc-48eb-b4ed-cac143d3f447
Gale, Phil
c840b7e9-6847-4843-91af-fa0f8563d943
Shin, Injae
486117e1-e1ed-4ef6-95c2-2f8dd45f1c23

Busschaert, Nathalie, Park, Seong-Hyun, Baek, Kyung-Hwa, Choi, Soon Pyo, Park, Jinhong, Howe, Ethan, Hiscock, Jennifer, Karagiannidis, Louise, Marques, Igor, Felix, Vitor, Namkung, Wan, Sessler, Jonathan, Gale, Phil and Shin, Injae (2017) A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations. Nature Chemistry, 9, 667–675. (doi:10.1038/nchem.2706).

Record type: Article

Abstract

Perturbations in cellular chloride concentrations can affect cellular pH, 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 the 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.

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squaramide-text-final-Nov16-submitted.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 17 November 2016
e-pub ahead of print date: 30 January 2017
Additional Information: Funded by Royal Society: Royal Society Wolfson Research Merit Award
Organisations: Organic Chemistry: SCF

Identifiers

Local EPrints ID: 403055
URI: https://eprints.soton.ac.uk/id/eprint/403055
ISSN: 1755-4330
PURE UUID: 3a21aec3-4fb4-4d37-b8de-435cd5bb8fe2
ORCID for Phil Gale: ORCID iD orcid.org/0000-0001-9751-4910

Catalogue record

Date deposited: 22 Nov 2016 16:31
Last modified: 15 Aug 2019 05:13

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Contributors

Author: Nathalie Busschaert
Author: Seong-Hyun Park
Author: Kyung-Hwa Baek
Author: Soon Pyo Choi
Author: Jinhong Park
Author: Ethan Howe
Author: Jennifer Hiscock
Author: Louise Karagiannidis
Author: Igor Marques
Author: Vitor Felix
Author: Wan Namkung
Author: Jonathan Sessler
Author: Phil Gale ORCID iD
Author: Injae Shin

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