ADAM12 promotes temozolomide resistance in glioblastoma by activating the TNF-α - NF-κB pathway

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-04-01 DOI:10.1016/j.canlet.2025.217684

Chunchao Cheng , Longtao Cui , Xiaoteng Cui , Qi Zhan , Jiasheng Ju , Biao Hong , Yanping Huang , Yaqing Ding , Hanyi Xu , Tian Qiu , Chunsheng Kang , Xiaomin Liu , Qixue Wang , Liang Zeng

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引用次数: 0

Abstract

Development of temozolomide (TMZ) resistance is a critical factor contributing to a poor prognosis in glioma patients. TMZ resistance is also closely associated with the phosphorylation level of NF-κB, yet targeted inhibition of NF-κB activity in glioma can be leveraged to overcome TMZ resistance. ADAM12, a protein significantly overexpressed in glioma cells, is implicated in the pathogenesis and progression of glioma, yet its role in the development of TMZ resistance is completely understood. We found that knockdown of ADAM12 was shown to arrest the glioma cell cycle, enhance apoptosis, inhibit DNA damage repair mechanisms, and sensitize glioma cells to TMZ. Targeting ADAM12 in vivo was found to increase the sensitivity of glioma cells to TMZ. Survival analysis indicated that ADAM12 serves as a prognostic marker for TMZ treatment. Using ELISA and protein interaction predictions via docking simulation, we identified the TNF-α shedding function of ADAM12 as a critical regulator of glioma progression. Furthermore, in glioma cell lines with unmethylated MGMT, the knockdown of ADAM12 enhanced sensitivity to TMZ by inhibiting the TNF-α/NF-κB pathway and reducing MGMT expression. In all, these results demonstrated that ADAM12 aids in shedding of membrane-bound TNF-a to drive TMZ resistance in glioma.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.