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

Chia Hung Chien, Wen Bin Yang, Jian Ying Chuang, Jung Shun Lee, Wei An Liao, Chih Yuan Huang, Pin Yuan Chen, An Chih Wu, Shun Tai Yang, Chien Cheng Lai, Pei I. Chi, Jui Mei Chu, Siao Muk Cheng, Chan Chuan Liu, Daw Yang Hwang, Shang Hung Chen, Kwang Yu Chang

研究成果: Article同行評審

4 引文 斯高帕斯(Scopus)

摘要

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.

原文English
文章編號220
期刊Journal of Experimental and Clinical Cancer Research
41
發行號1
DOIs
出版狀態Published - 2022 12月

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究

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