| Title: |
STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| Authors: |
Janina Remy; Benedikt Linder; Ulrike Weirauch; Bryan W. Day; Brett W. Stringer; Christel Herold-Mende; Achim Aigner; Knut Krohn; Donat Kögel |
| Source: |
Cancers, Vol 14, Iss 339, p 339 (2022) |
| Publisher Information: |
MDPI AG |
| Publication Year: |
2022 |
| Collection: |
Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: |
STAT3; glioblastoma; pimozide; autophagy; autophagy-dependent cell death; lysosome; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; RC254-282 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.mdpi.com/2072-6694/14/2/339; https://doaj.org/toc/2072-6694; https://doaj.org/article/d0fe7b9febb3444e9c9a95b0e6648345 |
| DOI: |
10.3390/cancers14020339 |
| Availability: |
https://doi.org/10.3390/cancers14020339; https://doaj.org/article/d0fe7b9febb3444e9c9a95b0e6648345 |
| Accession Number: |
edsbas.9EC32109 |
| Database: |
BASE |