Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis
作者机构：Department of PharmacyXiangya HospitalCentral South UniversityChangsha 410008China Department of NeurosurgeryXiangya HospitalCentral South UniversityChangsha 410008China Department of PathologyXiangya HospitalCentral South UniversityChangsha 410008China Xiangya Cancer CenterXiangya HospitalCentral South UniversityChangsha 410008China Key Laboratory of Molecular Radiation Oncology Hunan ProvinceChangsha 410008China institute of Cancer ResearchNational Clinical Research Center for Geriatric Disorders(Xiangya)Xiangya HospitalCentral South UniversityChangsha 410008China
出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)
年 卷 期：2024年第9卷第4期
页 面：1637-1650页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported by grants from the National Natural Science Foundation of China (82272659,82030087) the Science and Technology Innovation Program of Hunan Province (2022RC1210,2021RC3029) the Hunan Provincial Natural Science Foundation Project (2022JJ30073,2021JC0002).
主 题：TMZ homeostasis impaired
摘 要：Temozolomide(TMZ)represents a standard-of-care chemotherapeutic agent in glioblastoma(GBM).However,the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma.Although specific innovative approaches,such as immunotherapy,have shown favorable clinical outcomes,the inherent invasiveness of most gliomas continues to make them challenging to treat.Consequently,there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development.This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors.A total of 648 proteins exhibiting significant differential expression were identified.Gene Set Enrichment Analysis(GSEA)unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups.Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate(IP3)kinase B(ITPKB)in the recurrence group,correlating with poor survival in glioma patients.In TMZ-resistant cells,the depletion of ITPKB led to an increase in reactive oxygen species(ROS)related to NADPH oxidase(NOX)activity and restored cell sensitivity to TMz.Mechanistically,the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination.This,in turn,elevated ITPKB stability and impaired ROS production.Furthermore,ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model.These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target forTMZ-resistant GBM.
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