國家衛生研究院 NHRI:Item 3990099045/14444
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    題名: SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
    作者: Chien, CH;Yang, WB;Chuang, JY;Lee, JS;Liao, WA;Huang, CY;Chen, PY;Wu, AC;Yang, ST;Lai, CC;Chi, PI;Chu, JM;Cheng, SM;Liu, CC;Hwang, DY;Chen, SH;Chang, KY
    貢獻者: National Institute of Cancer Research
    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.
    日期: 2022-07-13
    關聯: Journal of Experimental and Clinical Cancer Research. 2022 Jul 13;41:Article number 220.
    Link to: http://dx.doi.org/10.1186/s13046-022-02429-8
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1756-9966&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000824620000001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85133998864
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