Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death

Meyer, Nina; Henkel, Lisa; Linder, Benedikt; Zielke, Svenja; Tascher, Georg; Trautmann, Sandra; Geißlinger, Gerd; Münch, Christian; Fulda, Simone; Tegeder, Irmgard; Kögel, Donat

doi:10.1080/15548627.2021.1874208

Cited by 58 publications

(46 citation statements)

References 82 publications

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“…After successfully confirming the biological applicability of these STAT3-KO cells we analyzed whether loss of STAT3 may influence the sensitivity of the cells to pro-death autophagy and LMP by using recently described ADLCD-inducing drugs consisting of (1) a combination treatment of imipramine and ticlopidine (IM + TIC) [ 48 ], which served as a positive control throughout the experiments; (2) Pimozide (Pimo) and (3) STF-62247 (STF) [ 38 , 49 ]. Accordingly, either treatment led to reduced cell death induction in all three KO-lines, indicating that loss of STAT3 mitigates this cell death response.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we showed that the proteomic profiles of MZ-54 cells treated with the ADLCD-inducing drugs Pimo and IM + TIC displayed very similar changes [38], in particular in lipid metabolic processes (most pronounced in cholesterol metabolism) and lysosomal function. In line with the proteomic data, cholesterol accumulation in the lysosomes and perturbed lysosomal function including lysosomal membrane permeabilization (LMP) and ADLCD were observed after treatment with these drugs [38]. Given that the drugs used in this study have been previously shown to affect lipid metabolic processes and lysosomal function [38,57] and that these processes are also altered in STAT3-KO cells, we validated selected high-ranking candidate genes by qPCR using MZ-54 with STAT3-KO (Figure 3D) and additionally with STAT3-KD (Supplemental Figure S7C).…”

Section: Knockout Of Stat3 Confers Sensitivity To Lysosomal Membrane ...mentioning

confidence: 99%

“…The lysosomes have been fittingly described as the “suicide bags” of the cells, because of their low pH and content of acidic hydrolases which are able to degrade macromolecules [ 36 ]. Damage to the lysosomal membrane, for example through cationic amphiphilic drugs [ 37 , 38 ], can trigger lysosomal membrane permeabilization (LMP), causing lysosomal rupture and release of its content into the cytosol [ 39 ]. The concomitant release of lysosomal cathepsin proteases and hydrolytic enzymes can lead to a specific type of cell death termed lysosome-dependent cell death (LDCD), that depending on the extent of LMP can have necrotic, apoptotic or apoptosis-like features [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

“…Based on the findings suggesting both an increased lysosomal activity and concomitant lysosomal destabilization in certain tumors, these organelles might represent a double-edged sword and render cancer cells more prone to lysosome-targeting agents and LDCD via excessive activation of LMP [ 42 ]. In our recent work, we could demonstrate that the repurposed drug Pimozide (Pimo) that acts as a functional inhibitor of the lysosomal enzyme acid sphingomyelinase (FIASMA) stimulates autophagy, impairs lipid trafficking/metabolism and destabilizes lysosomes to induce LMP and a unique cell death modality with characteristics of both autophagy-dependent cell death (ADCD) and lysosome-dependent cell death (LDCD) [ 38 , 44 ]. Based on these features, we propose the term autophagy-dependent lysosomal cell death (ADLCD) for this particular mixed type of cellular demise.…”

Section: Introductionmentioning

confidence: 99%

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

Remy

Linder

Weirauch

et al. 2022

Cancers

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Knockout Of Stat3 Confers Sensitivity To Lysosomal Membrane ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Remy

Linder

Weirauch

et al. 2022

Cancers

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“…Autophagy-related protein 7(Atg7) can trigger regulatory cell death (RCD) in glioma and often serve as a target for inducing autophagic-dependent death. 43 Studies have shown that SIRT1 inhibition can inhibit tumor growth. 44 PRKAA2 is also known as AMP-activated protein kinase (AMPK) again.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-Dependent Ferroptosis-Related Signature is Closely Associated with the Prognosis and Tumor Immune Escape of Patients with Glioma

Sun¹,

Yan²,

Ma³

et al. 2022

IJGM

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Background:Ferroptosis is an autophagy-dependent form of cell death, sometimes called "ferritinophagy". Its related pathway has been proven to regulate the programmed death of glioma stem cells. Mining autophagy-dependent ferroptosis-related gene (AD-FRG) signature could facilitate the discovery of mechanisms and therapeutic targets showing drug resistance to chemotherapeutic drugs. Methods: We exhaustively searched HADB, MSigDB and FerrDb datasets and obtained 25 genes confirmed to exist in autophagy and ferroptosis death pathways. Glioma gene expression and clinicopathological data were collected from TCGA and CGGA datasets. Results: Lasso regression and Cox regression analysis were carried out to construct a nine AD-FRGs signature (SIRT1, MTDH, HSPB1, CISD2, HMOX1, ATG7, MTOR, PRKAA2 and EIF2AK4). ROC curve showed that nine genes signature could effectively predict 1-(AUC = 0.869), 3-(AUC = 0.922) and 5-year (AUC = 0.870) survival rates. Immunohistochemical images confirmed the protein expression level of the gene model. The prognostic nomogram of risk score, age, WHO grade, isocitrate dehydrogenase (IDH) wild-type condition, 1p/19q co-deletion state was built. The calibration curve demonstrated that the prediction of the nomogram is highly consistent with the actual results. Moreover, tumor microenvironment analysis showed that the high-risk group was associated with high immune infiltration status and high tumor purity. Correlation analysis showed that the expression of SIRT1, CISD2 and HSPB1 might be related to macrophage infiltration and immunotolerance in glioma tissues. Conclusion: Based on autophagy-dependent ferroptosis-related genes, we established gene signature and nomogram that maybe effectively predict the overall survival rate of glioma and correlate with the immunosuppressive tumor microenvironment (TME).

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Targeting lysosomal HSP70 induces acid sphingomyelinase‐mediated disturbance of lipid metabolism and leads to cell death in T cell malignancies

Qing

Guo

Zhao

et al. 2023

Clinical & Translational Med

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Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death

Cited by 58 publications

References 82 publications

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

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

Autophagy-Dependent Ferroptosis-Related Signature is Closely Associated with the Prognosis and Tumor Immune Escape of Patients with Glioma

Targeting lysosomal HSP70 induces acid sphingomyelinase‐mediated disturbance of lipid metabolism and leads to cell death in T cell malignancies

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