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SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma

BACKGROUND: The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. METHODS: RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was m...

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Autores principales: Chien, Chia-Hung, Yang, Wen-Bin, Chuang, Jian-Ying, Lee, Jung-Shun, Liao, Wei-An, Huang, Chih-Yuan, Chen, Pin-Yuan, Wu, An-Chih, Yang, Shun-Tai, Lai, Chien-Cheng, Chi, Pei-I, Chu, Jui-Mei, Cheng, Siao Muk, Liu, Chan-Chuan, Hwang, Daw-Yang, Chen, Shang-Hung, Chang, Kwang-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281043/
https://www.ncbi.nlm.nih.gov/pubmed/35831908
http://dx.doi.org/10.1186/s13046-022-02429-8
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author Chien, Chia-Hung
Yang, Wen-Bin
Chuang, Jian-Ying
Lee, Jung-Shun
Liao, Wei-An
Huang, Chih-Yuan
Chen, Pin-Yuan
Wu, An-Chih
Yang, Shun-Tai
Lai, Chien-Cheng
Chi, Pei-I
Chu, Jui-Mei
Cheng, Siao Muk
Liu, Chan-Chuan
Hwang, Daw-Yang
Chen, Shang-Hung
Chang, Kwang-Yu
author_facet Chien, Chia-Hung
Yang, Wen-Bin
Chuang, Jian-Ying
Lee, Jung-Shun
Liao, Wei-An
Huang, Chih-Yuan
Chen, Pin-Yuan
Wu, An-Chih
Yang, Shun-Tai
Lai, Chien-Cheng
Chi, Pei-I
Chu, Jui-Mei
Cheng, Siao Muk
Liu, Chan-Chuan
Hwang, Daw-Yang
Chen, Shang-Hung
Chang, Kwang-Yu
author_sort Chien, Chia-Hung
collection PubMed
description BACKGROUND: The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. METHODS: RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was manipulated using RNA interference or gene amplification. Autophagic activity and mitochondrial metabolism was assessed in vitro using the respective cellular and molecular assays. In vivo analysis were also carried out in this study. RESULTS: High SH3GLB1 gene expression was found to be associated with higher disease grading and worse survival profiles. Single-cell transcriptome analysis of clinical samples suggested that SH3GLB1 and the altered gene levels of oxidative phosphorylation (OXPHOS) were related to subsets expressing a tumor-initiating cell signature. The SH3GLB1 protein was regulated by promoter binding with Sp1, a factor associated with TMZ resistance. Downregulation of SH3GLB1 resulted in retention of TMZ susceptibility, upregulated p62, and reduced LC3B-II. Autophagy inhibition by SH3GLB1 deficiency and chloroquine resulted in attenuated OXPHOS expression. Inhibition of SH3GLB1 in resistant cells resulted in alleviation of TMZ-enhanced mitochondrial metabolic function, such as mitochondrial membrane potential, mitochondrial respiration, and ATP production. SH3GLB1 modulation could determine tumor susceptibility to TMZ. Finally, in animal models, resistant tumor cells with SH3GLB1 knockdown became resensitized to the anti-tumor effect of TMZ, including the suppression of TMZ-induced autophagy and OXPHOS. CONCLUSIONS: SH3GLB1 promotes TMZ resistance via autophagy to alter mitochondrial function. Characterizing SH3GLB1 in glioblastoma may help develop new therapeutic strategies against this disease in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02429-8.
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spelling pubmed-92810432022-07-15 SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma Chien, Chia-Hung Yang, Wen-Bin Chuang, Jian-Ying Lee, Jung-Shun Liao, Wei-An Huang, Chih-Yuan Chen, Pin-Yuan Wu, An-Chih Yang, Shun-Tai Lai, Chien-Cheng Chi, Pei-I Chu, Jui-Mei Cheng, Siao Muk Liu, Chan-Chuan Hwang, Daw-Yang Chen, Shang-Hung Chang, Kwang-Yu J Exp Clin Cancer Res Research BACKGROUND: The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. METHODS: RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was manipulated using RNA interference or gene amplification. Autophagic activity and mitochondrial metabolism was assessed in vitro using the respective cellular and molecular assays. In vivo analysis were also carried out in this study. RESULTS: High SH3GLB1 gene expression was found to be associated with higher disease grading and worse survival profiles. Single-cell transcriptome analysis of clinical samples suggested that SH3GLB1 and the altered gene levels of oxidative phosphorylation (OXPHOS) were related to subsets expressing a tumor-initiating cell signature. The SH3GLB1 protein was regulated by promoter binding with Sp1, a factor associated with TMZ resistance. Downregulation of SH3GLB1 resulted in retention of TMZ susceptibility, upregulated p62, and reduced LC3B-II. Autophagy inhibition by SH3GLB1 deficiency and chloroquine resulted in attenuated OXPHOS expression. Inhibition of SH3GLB1 in resistant cells resulted in alleviation of TMZ-enhanced mitochondrial metabolic function, such as mitochondrial membrane potential, mitochondrial respiration, and ATP production. SH3GLB1 modulation could determine tumor susceptibility to TMZ. Finally, in animal models, resistant tumor cells with SH3GLB1 knockdown became resensitized to the anti-tumor effect of TMZ, including the suppression of TMZ-induced autophagy and OXPHOS. CONCLUSIONS: SH3GLB1 promotes TMZ resistance via autophagy to alter mitochondrial function. Characterizing SH3GLB1 in glioblastoma may help develop new therapeutic strategies against this disease in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02429-8. BioMed Central 2022-07-13 /pmc/articles/PMC9281043/ /pubmed/35831908 http://dx.doi.org/10.1186/s13046-022-02429-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Chien, Chia-Hung
Yang, Wen-Bin
Chuang, Jian-Ying
Lee, Jung-Shun
Liao, Wei-An
Huang, Chih-Yuan
Chen, Pin-Yuan
Wu, An-Chih
Yang, Shun-Tai
Lai, Chien-Cheng
Chi, Pei-I
Chu, Jui-Mei
Cheng, Siao Muk
Liu, Chan-Chuan
Hwang, Daw-Yang
Chen, Shang-Hung
Chang, Kwang-Yu
SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
title SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
title_full SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
title_fullStr SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
title_full_unstemmed SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
title_short SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
title_sort sh3glb1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281043/
https://www.ncbi.nlm.nih.gov/pubmed/35831908
http://dx.doi.org/10.1186/s13046-022-02429-8
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