| Title: |
STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| Authors: |
Remy, Janina; Linder, Benedikt; Weirauch, Ulrike; Day, Bryan W.; Stringer, Brett W.; Herold-Mende, Christel; Aigner, Achim; Krohn, Knut; Kögel, Donat |
| Publisher Information: |
MDPI |
| Publication Year: |
2022 |
| Collection: |
Universität Leipzig: Qucosa |
| Subject Terms: |
STAT3; glioblastoma; pimozide; autophagy; autophagy-dependent cell death; lysosome; lysosomal-dependent cell death; info:eu-repo/classification/ddc/610; ddc:610 |
| Description: |
Simple Summary Glioblastoma is the most common primary brain cancer in adults. One reason for the development and malignancy of this tumor is the misregulation of certain cellular proteins. The oncoprotein STAT3 that is frequently overactive in glioblastoma cells is associated with more aggressive disease and decreased patient survival. Autophagy is a form of cellular self digestion that normally maintains cell integrity and provides nutrients and basic building blocks required for growth. While glioblastoma is known to be particularly resistant to conventional therapies, recent research has suggested that these tumors are more sensitive to excessive overactivation of autophagy, leading to autophagy-dependent tumor cell death. Here, we show a hitherto unknown role of STAT3 in sensitizing glioblastoma cells to excessive autophagy induced with the repurposed drug pimozide. These findings provide the basis for future research aimed at determining whether STAT3 can serve as a predictor for autophagy-proficient tumors and further support the notion of overactivating autophagy for cancer therapy. Abstract 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2072-6694 |
| Relation: |
339; https://ul.qucosa.de/id/qucosa%3A85699 |
| Availability: |
https://nbn-resolving.org/urn:nbn:de:bsz:15-qucosa2-856991; https://ul.qucosa.de/id/qucosa%3A85699; https://ul.qucosa.de/api/qucosa%3A85699/attachment/ATT-0/ |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.BEFCFC89 |
| Database: |
BASE |