STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death

Cancers

Brett W. Stringer¹  Knut Krohn²  Christel Herold-Mende³  Janina Remy⁴  Benedikt Linder⁴  Donat Kögel⁴  Ulrike Weirauch⁵  Achim Aigner⁵  Bryan W. Day⁶ 

[1] College of Medicine and Public Health, Flinders University, Sturt Rd., Bedford Park, SA 5042, Australia;Core Unit DNA-Technologies, IZKF, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany;Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany;Neuroscience Center, Experimental Neurosurgery, Department of Neurosurgery, Goethe University Hospital, 60590 Frankfurt am Main, Germany;Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, 04103 Leipzig, Germany;Sid Faithful Brain Cancer Laboratory, QIMR Berghofer, Herston, QLD 4006, Australia;

关键词: STAT3;    glioblastoma;    pimozide;    autophagy;    autophagy-dependent cell death;    lysosome;   

DOI  :  10.3390/cancers14020339

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown