Gao, Zijie; Xu, Jianye; Fan, Yang; Qi, Yanhua; Wang, Shaobo; Zhao, Shulin; Guo, Xing; Xue, Hao; Deng, Lin; Zhao, Rongrong; Sun, Chong; Zhang, Ping; Li, Gang published the artcile< PDIA3P1 promotes Temozolomide resistance in glioblastoma by inhibiting C/EBPå°?degradation to facilitate proneural-to-mesenchymal transition>, Product Details of C19H34O2, the main research area is C/EBPå°? Glioma stem cells; MDM2; Neflamapimod; PDIA3P1; Proneural-to-mesenchymal transition; Temozolomide.
Abstract: Background: Resistance to temozolomide (TMZ) is a major obstacle to preventing glioblastoma (GBM) recurrence after surgery. Although long noncoding RNAs (lncRNAs) play a variety of roles in GBM, the lncRNAs that regulate TMZ resistance have not yet been clearly elucidated. This study aims to identify lncRNAs that may affect TMZ treatment sensitivity and to explore novel therapeutic strategies to overcome TMZ resistance in GBM. Methods: LncRNAs associated with TMZ resistance were identified using the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Quant. real-time PCR (qRT-PCR) was used to determine the expression of PDIA3P1 in TMZ-resistant and TMZ-sensitive GBM cell lines. Both gain-of-function and loss-of-function studies were used to assess the effects of PDIA3P1 on TMZ resistance using in vitro and in vivo assays. Glioma stem cells (GSCs) were used to determine the effect of PDIA3P1 on the GBM subtype. The hypothesis that PDIA3P1 promotes proneural-to-mesenchymal transition (PMT) was established using bioinformatics anal. and functional experiments RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between PDIA3P1 and C/EBPå°? The posttranslational modification mechanism of C/EBPå°?was verified using ubiquitination and coimmunoprecipitation (co-IP) experiments CompuSyn was leveraged to calculate the combination index (CI), and the antitumor effect of TMZ combined with nefllamapimod (NEF) was validated both in vitro and in vivo. Results: We identified a lncRNA, PDIA3P1, which was upregulated in TMZ-resistant GBM cell lines. Overexpression of PDIA3P1 promoted the acquisition of TMZ resistance, whereas knockdown of PDIA3P1 restored TMZ sensitivity. PDIA3P1 was upregulated in MES-GBM, promoted PMT progression in GSCs, and caused GBMs to be more resistant to TMZ treatment. Mechanistically, PDIA3P1 disrupted the C/EBPå°?MDM2 complex and stabilized the C/EBPå°?protein by preventing MDM2-mediated ubiquitination. Expression of PDIA3P1 was upregulated in a time- and concentration-dependent manner in response to TMZ treatment, and TMZ-induced upregulation of PDIA3P1 was mediated by the p38ä¼?MAPK signaling pathway. NEF is a small mol. drug that specifically targets p38ä¼?with excellent blood-brain barrier (BBB) permeability. NEF blocked TMZ-responsive PDIA3P1 upregulation and produced synergistic effects when combined with TMZ at specific concentrations The combination of TMZ and NEF exhibited excellent synergistic antitumor effects both in vitro and in vivo. Conclusion: PDIA3P1 promotes PMT by stabilizing C/EBPå°? reducing the sensitivity of GBM cells to TMZ treatment. NEF inhibits TMZ-responsive PDIA3P1 upregulation, and NEF combined with TMZ provides better antitumor effects.
Journal of Experimental & Clinical Cancer Research published new progress about 112-63-0. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Product Details of C19H34O2.
Referemce:
Ester – Wikipedia,
Ester – an overview | ScienceDirect Topics