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Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells

Glioblastoma (GBM) is the most common and aggressive type of brain cancer in adults, with temozolomide (TMZ) being widely used as the standard chemotherapy drug for its treatment. However, GBM frequently becomes resistant to TMZ treatment due to various mechanisms including amplification and mutatio...

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Autores principales: Chen, Yongqiang, Gibson, Spencer B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926073/
https://www.ncbi.nlm.nih.gov/pubmed/35309946
http://dx.doi.org/10.3389/fcell.2022.823251
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author Chen, Yongqiang
Gibson, Spencer B.
author_facet Chen, Yongqiang
Gibson, Spencer B.
author_sort Chen, Yongqiang
collection PubMed
description Glioblastoma (GBM) is the most common and aggressive type of brain cancer in adults, with temozolomide (TMZ) being widely used as the standard chemotherapy drug for its treatment. However, GBM frequently becomes resistant to TMZ treatment due to various mechanisms including amplification and mutations of the epidermal growth factor receptor (EGFR), where EGFR variant III (EGFRvIII) is the most common EGFR mutation. Autophagy (macroautophagy) is an intracellular “self-degradation” process involving the lysosome. It mainly plays a pro-cell survival role contributing to drug resistance in cancers including GBM, but, under some conditions, it can induce cell death called autophagy-induced cell death (AuICD). We recently published that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor and a novel autophagy inhibitor that inhibits cancer cell growth through its interacting with the autophagy protein LC3. In this brief research report, we demonstrate that cell death induced by TMZ in GBM cells is inhibited by overexpression of TSSC4. TSSC4 overexpression also prevents TMZ-induced autophagy but not when TSSC4 is mutated in its conserved LC3-interacting region. When EGFRvIII was expressed in GBM cells, TSSC4 protein was increased and TMZ-induced cell death was decreased. Knockout of TSSC4 in EGFRvIII-expressing GBM cells increased TMZ-induced autophagy and cell death. This cell death was decreased by autophagy inhibition, suggesting that TSSC4 downregulation promotes TMZ-induced AuICD. This indicates that TSSC4 is a novel target to sensitize GBM cells to TMZ treatment.
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spelling pubmed-89260732022-03-17 Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells Chen, Yongqiang Gibson, Spencer B. Front Cell Dev Biol Cell and Developmental Biology Glioblastoma (GBM) is the most common and aggressive type of brain cancer in adults, with temozolomide (TMZ) being widely used as the standard chemotherapy drug for its treatment. However, GBM frequently becomes resistant to TMZ treatment due to various mechanisms including amplification and mutations of the epidermal growth factor receptor (EGFR), where EGFR variant III (EGFRvIII) is the most common EGFR mutation. Autophagy (macroautophagy) is an intracellular “self-degradation” process involving the lysosome. It mainly plays a pro-cell survival role contributing to drug resistance in cancers including GBM, but, under some conditions, it can induce cell death called autophagy-induced cell death (AuICD). We recently published that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor and a novel autophagy inhibitor that inhibits cancer cell growth through its interacting with the autophagy protein LC3. In this brief research report, we demonstrate that cell death induced by TMZ in GBM cells is inhibited by overexpression of TSSC4. TSSC4 overexpression also prevents TMZ-induced autophagy but not when TSSC4 is mutated in its conserved LC3-interacting region. When EGFRvIII was expressed in GBM cells, TSSC4 protein was increased and TMZ-induced cell death was decreased. Knockout of TSSC4 in EGFRvIII-expressing GBM cells increased TMZ-induced autophagy and cell death. This cell death was decreased by autophagy inhibition, suggesting that TSSC4 downregulation promotes TMZ-induced AuICD. This indicates that TSSC4 is a novel target to sensitize GBM cells to TMZ treatment. Frontiers Media S.A. 2022-03-02 /pmc/articles/PMC8926073/ /pubmed/35309946 http://dx.doi.org/10.3389/fcell.2022.823251 Text en Copyright © 2022 Chen and Gibson. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Chen, Yongqiang
Gibson, Spencer B.
Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells
title Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells
title_full Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells
title_fullStr Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells
title_full_unstemmed Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells
title_short Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells
title_sort tumor suppressing subtransferable candidate 4 expression prevents autophagy-induced cell death following temozolomide treatment in glioblastoma cells
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926073/
https://www.ncbi.nlm.nih.gov/pubmed/35309946
http://dx.doi.org/10.3389/fcell.2022.823251
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