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dc.contributor.authorBartel, Karin
dc.contributor.authorMüller, Rolf
dc.contributor.authorvon Schwarzenberg, Karin
dc.date.accessioned2019-11-14T15:30:57Z
dc.date.available2019-11-14T15:30:57Z
dc.date.issued2019-10-11
dc.identifier.citationJ Biol Chem. 2019 Oct 11. pii: RA119.010243. doi: 10.1074/jbc.RA119.010243en_US
dc.identifier.issn1083-351X
dc.identifier.pmid31604821
dc.identifier.doi10.1074/jbc.RA119.010243
dc.identifier.urihttp://hdl.handle.net/10033/622016
dc.description.abstractThe cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic hub regulating various pathways involved in tumor metabolism. Here, we report that vacuolar H+-ATPase (V-ATPase) inhibition differentially affects regulation of AMPK in tumor and non-tumor cells and that this differential regulation contributes to the selectivity of V-ATPase inhibitors for tumor cells. In non-malignant cells, the V-ATPase inhibitor archazolid increased phosphorylation and lysosomal localization of AMPK. We noted that AMPK localization has a pro-survival role, as AMPK silencing decreased cellular growth rates. In contrast, in cancer cells, we found that AMPK is constitutively active and that archazolid does not affect its phosphorylation and localization. Moreover, V-ATPase-independent AMPK induction in the tumor cells protected them from archazolid-induced cytotoxicity, further underlining the role of AMPK as a pro-survival mediator. These observations indicate that AMPK regulation is uncoupled from V-ATPase activity in cancer cells and that this makes them more susceptible to cell death induction by V-ATPase inhibitors. In both tumor and healthy cells, V-ATPase inhibition induced a distinct metabolic regulatory cascade downstream of AMPK, affecting ATP and NADPH levels, glucose uptake, and reactive oxygen species (ROS) production. We could attribute the pro-survival effects to AMPK's ability to maintain redox homeostasis by inhibiting ROS production and maintaining NADPH levels. In summary, the results of our work indicate that V-ATPase inhibition has differential effects on AMPK-mediated metabolic regulation in cancer and healthy cells and explain the tumor-specific cytotoxicity of V-ATPase inhibition.en_US
dc.language.isoenen_US
dc.publisherAmerican Society for biochemistry and Molecular Biologyen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectAMP-activated kinase (AMPK)en_US
dc.subjectapoptosisen_US
dc.subjectarchazoliden_US
dc.subjectcanceren_US
dc.subjectglucose starvationen_US
dc.subjectmetabolismen_US
dc.subjectpH homeostasisen_US
dc.subjectreactive oxygen species (ROS)en_US
dc.subjecttumor suppressoren_US
dc.subjectvacuolar ATPaseen_US
dc.titleDifferential regulation of AMP-activated protein kinase in healthy and cancer cells explains why V-ATPase inhibition selectively kills cancer cells.en_US
dc.typeArticleen_US
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalJournal of biological chemistryen_US
dc.source.journaltitleThe Journal of biological chemistry


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