STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death
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 i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/339 |
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| author | Janina Remy Benedikt Linder Ulrike Weirauch Bryan W. Day Brett W. Stringer Christel Herold-Mende Achim Aigner Knut Krohn Donat Kögel |
| author_facet | Janina Remy Benedikt Linder Ulrike Weirauch Bryan W. Day Brett W. Stringer Christel Herold-Mende Achim Aigner Knut Krohn Donat Kögel |
| author_sort | Janina Remy |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T01:47:30Z |
| format | Article |
| id | doaj.art-d0fe7b9febb3444e9c9a95b0e6648345 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:47:30Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d0fe7b9febb3444e9c9a95b0e66483452023-11-23T13:13:21ZengMDPI AGCancers2072-66942022-01-0114233910.3390/cancers14020339STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell DeathJanina Remy0Benedikt Linder1Ulrike Weirauch2Bryan W. Day3Brett W. Stringer4Christel Herold-Mende5Achim Aigner6Knut Krohn7Donat Kögel8Neuroscience Center, Experimental Neurosurgery, Department of Neurosurgery, Goethe University Hospital, 60590 Frankfurt am Main, GermanyNeuroscience Center, Experimental Neurosurgery, Department of Neurosurgery, Goethe University Hospital, 60590 Frankfurt am Main, GermanyRudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, 04103 Leipzig, GermanySid Faithful Brain Cancer Laboratory, QIMR Berghofer, Herston, QLD 4006, AustraliaCollege of Medicine and Public Health, Flinders University, Sturt Rd., Bedford Park, SA 5042, AustraliaDivision of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, GermanyRudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, 04103 Leipzig, GermanyCore Unit DNA-Technologies, IZKF, Faculty of Medicine, University of Leipzig, 04103 Leipzig, GermanyNeuroscience Center, Experimental Neurosurgery, Department of Neurosurgery, Goethe University Hospital, 60590 Frankfurt am Main, GermanyGlioblastoma (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.https://www.mdpi.com/2072-6694/14/2/339STAT3glioblastomapimozideautophagyautophagy-dependent cell deathlysosome |
| spellingShingle | Janina Remy Benedikt Linder Ulrike Weirauch Bryan W. Day Brett W. Stringer Christel Herold-Mende Achim Aigner Knut Krohn Donat Kögel STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death Cancers STAT3 glioblastoma pimozide autophagy autophagy-dependent cell death lysosome |
| title | STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| title_full | STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| title_fullStr | STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| title_full_unstemmed | STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| title_short | STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death |
| title_sort | stat3 enhances sensitivity of glioblastoma to drug induced autophagy dependent cell death |
| topic | STAT3 glioblastoma pimozide autophagy autophagy-dependent cell death lysosome |
| url | https://www.mdpi.com/2072-6694/14/2/339 |
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