Zhang Yuyan, Guo Huiling, Bu Jiahao, Wang Weiwei, Wang Li, Liu Zhibo, Qiu Yuning, Wang Qimeng, Zhou Lijuan, Liu Xianzhi, Ma Liwei, Wei Jianwei
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
CNS Neurosci Ther. 2025 Jan;31(1):e70168. doi: 10.1111/cns.70168.
Resistance to temozolomide (TMZ) remains is an important cause of treatment failure in patients with glioblastoma multiforme (GBM). ADAR1, as a member of the ADAR family, plays an important role in cancer progression and chemotherapy resistance. However, the mechanism by which ADAR1 regulates GBM progression and TMZ resistance is still unclear.
We first constructed stable transfected strains in which ADAR1 was knocked down and overexpressed to investigate the effect of ADAR1 on the first-line glioma chemotherapy drug TMZ. Subsequently, we validated that ADAR1 induces autophagy activation and used autophagy inhibitors to suppress autophagy, demonstrating that ADAR1 enhances TMZ resistance through autophagy. We further knocked down p62 (SQSTM1) based on the overexpression of ADAR1, and the results showed that ADAR1 regulates selective autophagy through the p62 regulation. Finally, we demonstrated through mutations at both edited and nonedited sites that ADAR1 regulates selective autophagy in an edited dependent way.
Further analysis showed that in the presence of TMZ, elevated ADAR1 promoted TMZ induced autophagy activation. Further research revealed that ADAR1 enhances TMZ resistance through p62-mediated selective autophagy. Further, ADAR1 regulates selective autophagy in an edited dependent way. Our results indicate a relationship between ADAR1 levels and the response of glioma patients to TMZ treatment.
We found that the expression of ADAR1 is upregulated in GBM and is associated with tumor grade and TMZ resistance. Elevated expression of ADAR1 predicts poor prognosis in GBM patients and promotes tumor growth in vivo or in vitro.
对替莫唑胺（TMZ）耐药仍然是多形性胶质母细胞瘤（GBM）患者治疗失败的重要原因。ADAR1作为ADAR家族的一员，在癌症进展和化疗耐药中起重要作用。然而，ADAR1调节GBM进展和TMZ耐药的机制仍不清楚。
我们首先构建了ADAR1基因敲低和过表达的稳定转染株，以研究ADAR1对一线胶质瘤化疗药物TMZ的影响。随后，我们验证了ADAR1诱导自噬激活，并使用自噬抑制剂抑制自噬，证明ADAR1通过自噬增强TMZ耐药性。我们进一步基于ADAR1的过表达敲低p62（SQSTM1），结果表明ADAR1通过p62调节来调控选择性自噬。最后，我们通过编辑位点和非编辑位点的突变证明，ADAR1以编辑依赖的方式调节选择性自噬。
进一步分析表明，在存在TMZ的情况下，ADAR1升高促进了TMZ诱导的自噬激活。进一步研究表明，ADAR1通过p62介导的选择性自噬增强TMZ耐药性。此外，ADAR1以编辑依赖的方式调节选择性自噬。我们的结果表明ADAR1水平与胶质瘤患者对TMZ治疗的反应之间存在关联。
我们发现GBM中ADAR1的表达上调，且与肿瘤分级和TMZ耐药相关。ADAR1表达升高预示GBM患者预后不良，并在体内或体外促进肿瘤生长。
