Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Anne Hamacher-Brady
- Henning A Stein
- Simon Turschner
- Ina Toegel
- Rodrigo Mora
- Nina Jennewein
- Thomas Efferth
- Roland Eils
- Nathan R Brady
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000287476400068&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1074/jbc.M110.210047
- eISSN
- 1083-351X
- Externe Identifier
- Clarivate Analytics Document Solution ID: 723AB
- PubMed Identifier: 21149439
- ISSN
- 0021-9258
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Paginierung
- 6587 - 6601
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Titel
- Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production
- Sub types
- Article
- Ausgabe der Zeitschrift
- 286
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Anne Hamacher-Brady
- Henning A Stein
- Simon Turschner
- Ina Toegel
- Rodrigo Mora
- Nina Jennewein
- Thomas Efferth
- Roland Eils
- Nathan R Brady
- DOI
- 10.1074/jbc.m110.210047
- ISSN
- 0021-9258
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- Journal of Biological Chemistry
- Sprache
- en
- Paginierung
- 6587 - 6601
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1074/jbc.m110.210047
- Datum der Datenerfassung
- 2022
- Titel
- Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production
- Ausgabe der Zeitschrift
- 286
Data source: Crossref
- Abstract
- The antimalarial agent artesunate (ART) activates programmed cell death (PCD) in cancer cells in a manner dependent on the presence of iron and the generation of reactive oxygen species. In malaria parasites, ART cytotoxicity originates from interactions with heme-derived iron within the food vacuole. The analogous digestive compartment of mammalian cells, the lysosome, similarly contains high levels of redox-active iron and in response to specific stimuli can initiate mitochondrial apoptosis. We thus investigated the role of lysosomes in ART-induced PCD and determined that in MCF-7 breast cancer cells ART activates lysosome-dependent mitochondrial outer membrane permeabilization. ART impacted endolysosomal and autophagosomal compartments, inhibiting autophagosome turnover and causing perinuclear clustering of autophagosomes, early and late endosomes, and lysosomes. Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced death, thus identifying lysosomal iron as the lethal source of reactive oxygen species upstream of mitochondrial outer membrane permeabilization. Moreover, lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling. ART killing did not involve activation of the BH3-only protein, Bid, yet ART enhanced TNF-mediated Bid cleavage. We additionally demonstrated the lysosomal PCD pathway in T47D and MDA-MB-231 breast cancer cells. Importantly, non-tumorigenic MCF-10A cells resisted ART-induced PCD. Together, our data suggest that ART triggers PCD via engagement of distinct, interconnected PCD pathways, with hierarchical signaling from lysosomes to mitochondria, suggesting a potential clinical use of ART for targeting lysosomes in cancer treatment.
- Addresses
- Division of Theoretical Bioinformatics, Applied Systems Biology Group, German Cancer Research Center, 69120 Heidelberg, Germany.
- Autoren
- Anne Hamacher-Brady
- Henning A Stein
- Simon Turschner
- Ina Toegel
- Rodrigo Mora
- Nina Jennewein
- Thomas Efferth
- Thomas Efferth
- Roland Eils
- Nathan R Brady
- DOI
- 10.1074/jbc.m110.210047
- eISSN
- 1083-351X
- Externe Identifier
- PubMed Identifier: 21149439
- PubMed Central ID: PMC3057810
- Open access
- false
- ISSN
- 0021-9258
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- The Journal of biological chemistry
- Schlüsselwörter
- Cell Line, Tumor
- Lysosomes
- Mitochondria
- Humans
- Breast Neoplasms
- Iron
- Reactive Oxygen Species
- Artemisinins
- Macrolides
- Chloroquine
- Enzyme Inhibitors
- Antimalarials
- Apoptosis
- Permeability
- Female
- Mitochondrial Membranes
- Artesunate
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2010
- Paginierung
- 6587 - 6601
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2010
- Titel
- Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 286
Files
http://www.jbc.org/article/S0021925820520346/pdf http://intl.jbc.org/cgi/reprint/286/8/6587.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21149439/pdf/?tool=EBI https://europepmc.org/articles/PMC3057810?pdf=render
Data source: Europe PubMed Central
- Abstract
- The antimalarial agent artesunate (ART) activates programmed cell death (PCD) in cancer cells in a manner dependent on the presence of iron and the generation of reactive oxygen species. In malaria parasites, ART cytotoxicity originates from interactions with heme-derived iron within the food vacuole. The analogous digestive compartment of mammalian cells, the lysosome, similarly contains high levels of redox-active iron and in response to specific stimuli can initiate mitochondrial apoptosis. We thus investigated the role of lysosomes in ART-induced PCD and determined that in MCF-7 breast cancer cells ART activates lysosome-dependent mitochondrial outer membrane permeabilization. ART impacted endolysosomal and autophagosomal compartments, inhibiting autophagosome turnover and causing perinuclear clustering of autophagosomes, early and late endosomes, and lysosomes. Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced death, thus identifying lysosomal iron as the lethal source of reactive oxygen species upstream of mitochondrial outer membrane permeabilization. Moreover, lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling. ART killing did not involve activation of the BH3-only protein, Bid, yet ART enhanced TNF-mediated Bid cleavage. We additionally demonstrated the lysosomal PCD pathway in T47D and MDA-MB-231 breast cancer cells. Importantly, non-tumorigenic MCF-10A cells resisted ART-induced PCD. Together, our data suggest that ART triggers PCD via engagement of distinct, interconnected PCD pathways, with hierarchical signaling from lysosomes to mitochondria, suggesting a potential clinical use of ART for targeting lysosomes in cancer treatment.
- Autoren
- Anne Hamacher-Brady
- Henning A Stein
- Simon Turschner
- Ina Toegel
- Rodrigo Mora
- Nina Jennewein
- Thomas Efferth
- Roland Eils
- Nathan R Brady
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/21149439
- DOI
- 10.1074/jbc.M110.210047
- eISSN
- 1083-351X
- Externe Identifier
- PubMed Central ID: PMC3057810
- Ausgabe der Veröffentlichung
- 8
- Zeitschrift
- J Biol Chem
- Schlüsselwörter
- Antimalarials
- Apoptosis
- Artemisinins
- Artesunate
- Breast Neoplasms
- Cell Line, Tumor
- Chloroquine
- Enzyme Inhibitors
- Female
- Humans
- Iron
- Lysosomes
- Macrolides
- Mitochondria
- Mitochondrial Membranes
- Permeability
- Reactive Oxygen Species
- Sprache
- eng
- Country
- United States
- Paginierung
- 6587 - 6601
- PII
- S0021-9258(20)52034-6
- Datum der Veröffentlichung
- 2011
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2011
- Titel
- Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 286
Data source: PubMed
- Beziehungen:
- Property of