TY  - JOUR
A1  - Remy, Janina
A1  - Linder, Benedikt
A1  - Weirauch, Ulrike
A1  - Day, Bryan W.
A1  - Stringer, Brett W.
A1  - Herold-Mende, Christel
A1  - Aigner, Achim
A1  - Krohn, Knut
A1  - Kögel, Donat
T1  - STAT3 enhances sensitivity of glioblastoma to drug-induced autophagy-dependent cell death
T2  - Cancers
N2  - Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.
KW  - STAT3
KW  - glioblastoma
KW  - pimozide
KW  - autophagy
KW  - autophagy-dependent cell death
KW  - lysosome
KW  - lysosomal-dependent cell death
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/82100
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-821005
SN  - 2072-6694
N1  - This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft),—Project-ID 259130777—SFB 1177 E09 to D.K.; KO 1898 9/1 to D.K.; AI 24/13-1 to AA.
N1  - Deep sequencing datasets generated and analysed during the current study are available in the Gene Expression Omnibus (GEO) repository, accession number GSE162429.
N1  - Symbols for the Graphical Abstract were taken from Smart Servier Medical Art. Permission for reproduction of the symbols: Creative Commons Attribution 3.0 Unported (CC BY 3.0), https://smart.servier.com; accessed on: 10 April 2018).
VL  - 14
IS  - 2, art. 339
SP  - 1
EP  - 23
PB  - MDPI
CY  - Basel
ER  -