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Main Title: Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell death
Author(s): Klutzny, Saskia
Lesche, Ralf
Keck, Matthias
Kaulfuss, Stefan
Schlicker, Andreas
Christian, Sven
Sperl, Carolyn
Neuhaus, Roland
Mowat, Jeffrey
Steckel, Michael
Riefke, Björn
Prechtl, Stefan
Parczyk, Karsten
Steigemann, Patrick
Type: Article
Language Code: en
Is Part Of: 10.14279/depositonce-7215
Abstract: Owing 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.
Issue Date: 2017
Date Available: 19-Apr-2018
DDC Class: 570 Biowissenschaften; Biologie
Journal Title: Cell Death & Disease
Publisher: Springer Nature
Publisher Place: London [u.a.]
Volume: 8
Issue: 3
Article Number: e2709
Publisher DOI: 10.1038/cddis.2017.130
EISSN: 2041-4889
ISSN: 2041-4889
Appears in Collections:FG Bioanalytik » Publications

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