Mode of Cell Death Induction by Pharmacological Vacuolar H+-ATPase (V-ATPase) Inhibition
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Karin von Schwarzenberg
- Romina M Wiedmann
- Prajakta Oak
- Sabine Schulz
- Hans Zischka
- Gerhard Wanner
- Thomas Efferth
- Dirk Trauner
- Angelika M Vollmar
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000313570300059&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1074/jbc.M112.412007
- eISSN
- 1083-351X
- Externe Identifier
- Clarivate Analytics Document Solution ID: 071ES
- PubMed Identifier: 23168408
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Paginierung
- 1385 - 1396
- Datum der Veröffentlichung
- 2013
- Status
- Published
- Titel
- Mode of Cell Death Induction by Pharmacological Vacuolar H<SUP>+</SUP>-ATPase (V-ATPase) Inhibition
- Sub types
- Article
- Ausgabe der Zeitschrift
- 288
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Karin von Schwarzenberg
- Romina M Wiedmann
- Prajakta Oak
- Sabine Schulz
- Hans Zischka
- Gerhard Wanner
- Thomas Efferth
- Dirk Trauner
- Angelika M Vollmar
- DOI
- 10.1074/jbc.m112.412007
- ISSN
- 0021-9258
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Journal of Biological Chemistry
- Sprache
- en
- Paginierung
- 1385 - 1396
- Datum der Veröffentlichung
- 2013
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1074/jbc.m112.412007
- Datum der Datenerfassung
- 2021
- Titel
- Mode of Cell Death Induction by Pharmacological Vacuolar H+-ATPase (V-ATPase) Inhibition
- Ausgabe der Zeitschrift
- 288
Data source: Crossref
- Abstract
- The vacuolar H(+)-ATPase (V-ATPase), a multisubunit proton pump, has come into focus as an attractive target in cancer invasion. However, little is known about the role of V-ATPase in cell death, and especially the underlying mechanisms remain mostly unknown. We used the myxobacterial macrolide archazolid B, a potent inhibitor of the V-ATPase, as an experimental drug as well as a chemical tool to decipher V-ATPase-related cell death signaling. We found that archazolid induced apoptosis in highly invasive tumor cells at nanomolar concentrations which was executed by the mitochondrial pathway. Prior to apoptosis induction archazolid led to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1α (HIF1α) and autophagy. Autophagy, which was demonstrated by degradation of p62 or fusion of autophagosomes with lysosomes, was induced at low concentrations of archazolid that not yet increase pH in lysosomes. HIF1α was induced due to energy stress shown by a decline of the ATP level and followed by a shutdown of energy-consuming processes. As silencing HIF1α increases apoptosis, the cellular stress response was suggested to be a survival mechanism. We conclude that archazolid leads to energy stress which activates adaptive mechanisms like autophagy mediated by HIF1α and finally leads to apoptosis. We propose V-ATPase as a promising drugable target in cancer therapy caught up at the interplay of apoptosis, autophagy, and cellular/metabolic stress.
- Addresses
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, 81377 Munich, Germany. karin.von.schwarzenberg@cup.uni-muenchen.de
- Autoren
- Karin von Schwarzenberg
- Romina M Wiedmann
- Prajakta Oak
- Sabine Schulz
- Hans Zischka
- Gerhard Wanner
- Thomas Efferth
- Thomas Efferth
- Dirk Trauner
- Angelika M Vollmar
- DOI
- 10.1074/jbc.m112.412007
- eISSN
- 1083-351X
- Externe Identifier
- PubMed Identifier: 23168408
- PubMed Central ID: PMC3543021
- Open access
- false
- ISSN
- 0021-9258
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- The Journal of biological chemistry
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Cytochromes c
- Vacuolar Proton-Translocating ATPases
- Enzyme Inhibitors
- Microscopy, Confocal
- Signal Transduction
- Cell Death
- Cell Proliferation
- Autophagy
- Membrane Potential, Mitochondrial
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2012
- Paginierung
- 1385 - 1396
- Datum der Veröffentlichung
- 2013
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2012
- Titel
- Mode of cell death induction by pharmacological vacuolar H+-ATPase (V-ATPase) inhibition.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 288
Files
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23168408/pdf/?tool=EBI https://europepmc.org/articles/PMC3543021?pdf=render
Data source: Europe PubMed Central
- Abstract
- The vacuolar H(+)-ATPase (V-ATPase), a multisubunit proton pump, has come into focus as an attractive target in cancer invasion. However, little is known about the role of V-ATPase in cell death, and especially the underlying mechanisms remain mostly unknown. We used the myxobacterial macrolide archazolid B, a potent inhibitor of the V-ATPase, as an experimental drug as well as a chemical tool to decipher V-ATPase-related cell death signaling. We found that archazolid induced apoptosis in highly invasive tumor cells at nanomolar concentrations which was executed by the mitochondrial pathway. Prior to apoptosis induction archazolid led to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1α (HIF1α) and autophagy. Autophagy, which was demonstrated by degradation of p62 or fusion of autophagosomes with lysosomes, was induced at low concentrations of archazolid that not yet increase pH in lysosomes. HIF1α was induced due to energy stress shown by a decline of the ATP level and followed by a shutdown of energy-consuming processes. As silencing HIF1α increases apoptosis, the cellular stress response was suggested to be a survival mechanism. We conclude that archazolid leads to energy stress which activates adaptive mechanisms like autophagy mediated by HIF1α and finally leads to apoptosis. We propose V-ATPase as a promising drugable target in cancer therapy caught up at the interplay of apoptosis, autophagy, and cellular/metabolic stress.
- Autoren
- Karin von Schwarzenberg
- Romina M Wiedmann
- Prajakta Oak
- Sabine Schulz
- Hans Zischka
- Gerhard Wanner
- Thomas Efferth
- Dirk Trauner
- Angelika M Vollmar
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/23168408
- DOI
- 10.1074/jbc.M112.412007
- eISSN
- 1083-351X
- Externe Identifier
- PubMed Central ID: PMC3543021
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- J Biol Chem
- Schlüsselwörter
- Autophagy
- Cell Death
- Cell Line, Tumor
- Cell Proliferation
- Cytochromes c
- Enzyme Inhibitors
- Humans
- Membrane Potential, Mitochondrial
- Microscopy, Confocal
- Signal Transduction
- Vacuolar Proton-Translocating ATPases
- Sprache
- eng
- Country
- United States
- Paginierung
- 1385 - 1396
- PII
- S0021-9258(20)46681-5
- Datum der Veröffentlichung
- 2013
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2013
- Titel
- Mode of cell death induction by pharmacological vacuolar H+-ATPase (V-ATPase) inhibition.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 288
Data source: PubMed
- Beziehungen:
- Property of