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Article: PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer

TitlePPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer
Authors
Issue Date1-Feb-2019
PublisherAmerican Association for Cancer Research
Citation
Cancer Discovery, 2019, v. 9, n. 2 How to Cite?
Abstract

Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.

Significance:

This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer.


Persistent Identifierhttp://hdl.handle.net/10722/341649
ISSN
2023 Impact Factor: 29.7
2023 SCImago Journal Rankings: 7.533

 

DC FieldValueLanguage
dc.contributor.authorRebecca, VW-
dc.contributor.authorNicastri, MC-
dc.contributor.authorFennelly, C-
dc.contributor.authorChude, CI-
dc.contributor.authorBarber-Rotenberg, JS-
dc.contributor.authorRonghe, A-
dc.contributor.authorMcAfee, Q-
dc.contributor.authorMcLaughlin, NP-
dc.contributor.authorZhang, G-
dc.contributor.authorGoldman, AR-
dc.contributor.authorOjha, R-
dc.contributor.authorPiao, S-
dc.contributor.authorNoguera-Ortega, E-
dc.contributor.authorMartorella, A-
dc.contributor.authorAlicea, GM-
dc.contributor.authorLee, JJ-
dc.contributor.authorSchuchter, LM-
dc.contributor.authorXu, X-
dc.contributor.authorHerlyn, M-
dc.contributor.authorMarmorstein, R-
dc.contributor.authorGimotty, PA-
dc.contributor.authorSpeicher, DW-
dc.contributor.authorWinkler, JD-
dc.contributor.authorAmaravadi, RK-
dc.date.accessioned2024-03-20T06:58:00Z-
dc.date.available2024-03-20T06:58:00Z-
dc.date.issued2019-02-01-
dc.identifier.citationCancer Discovery, 2019, v. 9, n. 2-
dc.identifier.issn2159-8274-
dc.identifier.urihttp://hdl.handle.net/10722/341649-
dc.description.abstract<p>Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an <em>in situ</em> photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.</p><p>Significance:</p><p>This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer.</p>-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Discovery-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titlePPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer-
dc.typeArticle-
dc.identifier.doi10.1158/2159-8290.CD-18-0706-
dc.identifier.volume9-
dc.identifier.issue2-
dc.identifier.eissn2159-8290-
dc.identifier.issnl2159-8274-

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