Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide
Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide
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外泌体连接蛋白43调节神经胶质瘤细胞对替莫唑胺的耐药性
DOI：
10.3892/or.2021.7995
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发表时间：
2021-02
期刊：
影响因子：
4.2
通讯作者：
蒋丽萍
中科院分区：
文献类型：
--
作者：
杨章坚;张乐玲;毕秋臣;干丽君;魏敏君;洪涛;谈仁杰;兰雪梅;刘立华;韩小建;蒋丽萍
胶质母细胞瘤是最常见和侵袭性的脑肿瘤，其特点是死亡率高。替莫唑胺（Temozolomide， TMZ）是一种有效的胶质母细胞瘤化疗药物，但对TMZ的耐药已成为一个重要的临床问题，其潜在的机制尚未阐明。在本研究中，研究了外泌体连接蛋白43 （Cx43）在胶质瘤细胞对TMZ的抗性和细胞迁移中的作用。首先，与tmz敏感细胞（U251s）相比，tmz耐药细胞（U251r）中Cx43的表达水平更高。从U251s和U251r细胞（分别为sExo和rExo）分离外泌体。结果发现，Cx43在rExo中的表达明显高于sExo，而rExo处理则增加了U251s细胞中Cx43的表达。此外，用dioctadecyloxarbocyanine （Dio）染色的外泌体用于观察胶质瘤细胞对外泌体的摄取。我们观察到，与dio染色的sExo相比，dio染色的rExo在U251s细胞中的摄取更为突出，而37,43gap27是一种针对Cx43的间隙连接模拟肽，可以减轻细胞对rExo的摄取。此外，rExo增加了U251s细胞对TMZ的IC50、集落形成和Bcl-2的表达，降低了U251s细胞中Bax和cleaved - caspase-3的表达。37,43gap27有效抑制rExo对U251s细胞的这些作用。最后，伤口愈合和Transwell实验结果显示，rExo显著增强了U251s细胞的迁移，而37,43gap27显著减弱了rExo诱导的细胞迁移。综上所述，这些结果表明外泌体Cx43在胶质瘤细胞的化疗耐药和迁移中起着至关重要的作用，并表明Cx43可能在未来成为胶质母细胞瘤的治疗靶点。
Glioblastoma is the most common and aggressive brain tumor and it is characterized by a high mortality rate. Temozolomide (TMZ) is an effective chemotherapy drug for glioblastoma, but the resistance to TMZ has come to represent a major clinical problem, and its underlying mechanism has yet to be elucidated. In the present study, the role of exosomal connexin 43 (Cx43) in the resistance of glioma cells to TMZ and cell migration was investigated. First, higher expression levels of Cx43 were detected in TMZ-resistant U251 (U251r) cells compared with those in TMZ-sensitive (U251s) cells. Exosomes from U251s or U251r cells (sExo and rExo, respectively) were isolated. It was found that the expression of Cx43 in rExo was notably higher compared with that in sExo, whereas treatment with rExo increased the expression of Cx43 in U251s cells. Additionally, exosomes stained with dioctadecyloxacarbocyanine (Dio) were used to visualized exosome uptake by glioma cells. It was observed that the uptake of Dio-stained rExo in U251s cells was more prominent compared with that of Dio-stained sExo, while 37,43Gap27, a gap junction mimetic peptide directed against Cx43, alleviated the rExo uptake by cells. Moreover, rExo increased the IC50 of U251s to TMZ, colony formation and Bcl-2 expression, but decreased Bax and cleaved caspase-3 expression in U251s cells. 37,43Gap27 efficiently inhibited these effects of rExo on U251s cells. Finally, the results of the wound healing and Transwell assays revealed that rExo significantly enhanced the migration of U251s cells, whereas 37,43Gap27 significantly attenuated rExo-induced cell migration. Taken together, these results indicate the crucial role of exosomal Cx43 in chemotherapy resistance and migration of glioma cells, and suggest that Cx43 may hold promise as a therapeutic target for glioblastoma in the future.
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影响因子：
158.5
作者：
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通讯作者：
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影响因子：
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