Lysosomotropism depends on glucose: a chloroquine resistance mechanism

Laura E Gallagher, Ohood A Radhi, Mahmud O Abudullah, Anthony G McCluskey, Marie Boyd, Edmond Y W Chan

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

There has been long-standing interest in targeting pro-survival autophagy as a combinational cancer therapeutic strategy. Clinical trials are in progress testing Chloroquine (CQ) or its derivatives in combination with chemo- or radio-therapy for solid and haematological cancers. While CQ has shown efficacy in pre-clinical models, its mechanism of action remains equivocal. Here, we tested how effectively CQ sensitises metastatic breast cancer cells to further stress conditions such as ionising irradiation, doxorubicin, PI3K-Akt inhibition and serum withdrawal. Contrary to the conventional model, the cytotoxic effects of CQ were found to be autophagy-independent, since genetic targeting of ATG7 or the ULK1/2 complex could not sensitise cells, like CQ, to serum depletion. Interestingly, while CQ combined with serum starvation was robustly cytotoxic, further glucose starvation under these conditions led to a full rescue of cell viability. Inhibition of hexokinase using 2-deoxyglucose (2DG) similarly led to CQ resistance. As this form of cell death did not resemble classical caspase-dependent apoptosis, we hypothesised that CQ-mediated cytotoxicity was primarily via a lysosome-dependent mechanism. Indeed, CQ treatment led to marked lysosomal swelling and recruitment of Galectin3 to sites of membrane damage. Strikingly, glucose starvation or 2DG prevented CQ from inducing lysosomal damage and subsequent cell death. Importantly, we found that the related compound, amodiaquine, was more potent than CQ for cell killing and not susceptible to interference from glucose starvation. Taken together, our data indicate that CQ effectively targets the lysosome to sensitise towards cell death but is prone to a glucose-dependent resistance mechanism, thus providing rationale for the related compound amodiaquine (currently used in humans) as a better therapeutic option for cancer.
LanguageEnglish
Article numbere3014
Number of pages14
JournalCell Death and Disease
Volume8
DOIs
Publication statusPublished - 24 Aug 2017

Fingerprint

Chloroquine
Glucose
Starvation
Amodiaquine
Cell Death
Autophagy
Deoxyglucose
Lysosomes
Serum
Neoplasms
Hexokinase
Therapeutics
Caspases
Radio
Phosphatidylinositol 3-Kinases
Doxorubicin
Cell Survival
Clinical Trials
Apoptosis
Breast Neoplasms

Keywords

  • chloroquine
  • glucose starvation
  • lysosomotropism

Cite this

Gallagher, Laura E ; Radhi, Ohood A ; Abudullah, Mahmud O ; McCluskey, Anthony G ; Boyd, Marie ; Chan, Edmond Y W. / Lysosomotropism depends on glucose : a chloroquine resistance mechanism. In: Cell Death and Disease. 2017 ; Vol. 8.
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Lysosomotropism depends on glucose : a chloroquine resistance mechanism. / Gallagher, Laura E; Radhi, Ohood A; Abudullah, Mahmud O; McCluskey, Anthony G; Boyd, Marie; Chan, Edmond Y W.

In: Cell Death and Disease, Vol. 8, e3014, 24.08.2017.

Research output: Contribution to journalArticle

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T1 - Lysosomotropism depends on glucose

T2 - Cell Death and Disease

AU - Gallagher, Laura E

AU - Radhi, Ohood A

AU - Abudullah, Mahmud O

AU - McCluskey, Anthony G

AU - Boyd, Marie

AU - Chan, Edmond Y W

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AB - There has been long-standing interest in targeting pro-survival autophagy as a combinational cancer therapeutic strategy. Clinical trials are in progress testing Chloroquine (CQ) or its derivatives in combination with chemo- or radio-therapy for solid and haematological cancers. While CQ has shown efficacy in pre-clinical models, its mechanism of action remains equivocal. Here, we tested how effectively CQ sensitises metastatic breast cancer cells to further stress conditions such as ionising irradiation, doxorubicin, PI3K-Akt inhibition and serum withdrawal. Contrary to the conventional model, the cytotoxic effects of CQ were found to be autophagy-independent, since genetic targeting of ATG7 or the ULK1/2 complex could not sensitise cells, like CQ, to serum depletion. Interestingly, while CQ combined with serum starvation was robustly cytotoxic, further glucose starvation under these conditions led to a full rescue of cell viability. Inhibition of hexokinase using 2-deoxyglucose (2DG) similarly led to CQ resistance. As this form of cell death did not resemble classical caspase-dependent apoptosis, we hypothesised that CQ-mediated cytotoxicity was primarily via a lysosome-dependent mechanism. Indeed, CQ treatment led to marked lysosomal swelling and recruitment of Galectin3 to sites of membrane damage. Strikingly, glucose starvation or 2DG prevented CQ from inducing lysosomal damage and subsequent cell death. Importantly, we found that the related compound, amodiaquine, was more potent than CQ for cell killing and not susceptible to interference from glucose starvation. Taken together, our data indicate that CQ effectively targets the lysosome to sensitise towards cell death but is prone to a glucose-dependent resistance mechanism, thus providing rationale for the related compound amodiaquine (currently used in humans) as a better therapeutic option for cancer.

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