Leucine-rich repeat containing 4 act as an autophagy inhibitor that restores sensitivity of glioblastoma to temozolomide
Leucine-rich repeat containing 4 act as an autophagy inhibitor that restores sensitivity of glioblastoma to temozolomide
复制标题
含有 4 的富含亮氨酸重复序列可作为自噬抑制剂，恢复胶质母细胞瘤对替莫唑胺的敏感性
DOI：
10.1038/s41388-020-1312-6
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发表时间：
2020-05-05
期刊：
影响因子：
8
通讯作者：
Wu, Minghua
中科院分区：
文献类型：
--
作者：
Feng, Jianbo;Zhang, Yan;Wu, Minghua
替莫唑胺(TMZ)不敏感和耐药是GBM患者治疗失败和预后不良的主要原因。在这里，我们确定LRRC4是一种新的自噬抑制剂，可以恢复GBM对TMZ的敏感性。LRRC4与DEPTOR/mTOR复合体结合，这种相互作用导致自噬抑制。进一步的研究表明，LRRC4的PDZ结合域与DEPTOR的PDZ结构域结合。这种结合通过泛素化减少了DEPTOR的半衰期，从而抑制了GBM细胞的自噬，并增加了GBM对TMZ的治疗反应。LRRC4表达和TMZ联合治疗延长了荷瘤小鼠的存活时间。此外，LRRC4、DEPTOR和自噬水平与胶质瘤的发生密切相关，表明LRRC4有可能成为治疗胶质瘤患者TMZ的治疗标记物和靶点。
Temozolomide (TMZ) insensitivity and resistance are major causes of treatment failure and poor prognosis for GBM patients. Here, we identify LRRC4 as a novel autophagy inhibitor that restores the sensitivity of GBMs to TMZ. LRRC4 was associated with the DEPTOR/mTOR complex, and this interaction resulted in autophagy inhibition. Further investigation demonstrated that the PDZ binding domain of LRRC4 binds to the PDZ domain of DEPTOR. This binding decreases the half-life of DEPTOR via ubiquitination, thus inhibiting GBM cell autophagy and increasing the TMZ treatment response of GBM. Combined LRRC4 expression and TMZ treatment prolonged the survival of mice with tumour xenografts. Furthermore, the levels of LRRC4, DEPTOR and autophagy are clinically relevant for GBM, indicating that LRRC4 is likely to have significant potential as a therapeutic marker and target for TMZ treatment in glioma patients.