Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell death

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dc.contributor.authorKlutzny, Saskia
dc.contributor.authorLesche, Ralf
dc.contributor.authorKeck, Matthias
dc.contributor.authorKaulfuss, Stefan
dc.contributor.authorSchlicker, Andreas
dc.contributor.authorChristian, Sven
dc.contributor.authorSperl, Carolyn
dc.contributor.authorNeuhaus, Roland
dc.contributor.authorMowat, Jeffrey
dc.contributor.authorSteckel, Michael
dc.contributor.authorRiefke, Björn
dc.contributor.authorPrechtl, Stefan
dc.contributor.authorParczyk, Karsten
dc.contributor.authorSteigemann, Patrick
dc.date.accessioned2018-04-19T08:47:27Z
dc.date.available2018-04-19T08:47:27Z
dc.date.issued2017
dc.description.abstractOwing to lagging or insufficient neo-angiogenesis, hypoxia is a feature of most solid tumors. Hypoxic tumor regions contribute to resistance against antiproliferative chemotherapeutics, radiotherapy and immunotherapy. Targeting cells in hypoxic tumor areas is therefore an important strategy for cancer treatment. Most approaches for targeting hypoxic cells focus on the inhibition of hypoxia adaption pathways but only a limited number of compounds with the potential to specifically target hypoxic tumor regions have been identified. By using tumor spheroids in hypoxic conditions as screening system, we identified a set of compounds, including the phenothiazine antipsychotic Fluphenazine, as hits with novel mode of action. Fluphenazine functionally inhibits acid sphingomyelinase and causes cellular sphingomyelin accumulation, which induces cancer cell death specifically in hypoxic tumor spheroids. Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress-response pathways and that hypoxia-specific cell death is mediated by the stress-responsive transcription factor ATF4. Taken together, the here presented data suggest a novel, yet unexplored mechanism in which induction of sphingolipid stress leads to the overactivation of hypoxia stress-response pathways and thereby promotes their pro-apoptotic tumor-suppressor functions to specifically kill cells in hypoxic tumor areas.en
dc.identifier.eissn2041-4889
dc.identifier.issn2041-4889
dc.identifier.urihttps://depositonce.tu-berlin.de/handle/11303/7641
dc.identifier.urihttp://dx.doi.org/10.14279/depositonce-6831
dc.language.isoen
dc.relation.ispartof10.14279/depositonce-7215
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.ddc570 Biowissenschaften; Biologie
dc.titleFunctional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell deathen
dc.typeArticle
dc.type.versionpublishedVersionen
dcterms.bibliographicCitation.articlenumbere2709
dcterms.bibliographicCitation.doi10.1038/cddis.2017.130
dcterms.bibliographicCitation.issue3
dcterms.bibliographicCitation.journaltitleCell Death & Diseaseen
dcterms.bibliographicCitation.originalpublishernameSpringer Nature
dcterms.bibliographicCitation.originalpublisherplaceLondon [u.a.]
dcterms.bibliographicCitation.volume8
tub.accessrights.dnbfree
tub.affiliationFak. 3 Prozesswissenschaften::Inst. Biotechnologie::FG Bioanalytikde
tub.affiliation.facultyFak. 3 Prozesswissenschaftende
tub.affiliation.groupFG Bioanalytikde
tub.affiliation.instituteInst. Biotechnologiede
tub.publisher.universityorinstitutionTechnische Universität Berlinde

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