Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway
Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway
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DOI：
10.1016/j.neuropharm.2013.05.002
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发表时间：
2013-12-01
影响因子：
4.7
通讯作者：
Sin, Wun Chey
中科院分区：
文献类型：
--
作者：
Gielen, Paul R.;Aftab, Qurratulain;Sin, Wun Chey
多形性胶质母细胞瘤（GBM）是最具侵袭性的星形细胞瘤，治疗选择通常限于手术切除、放疗和替莫唑胺（TMZ）化疗。TMZ是一种DNA烷化剂，可导致DNA损伤并诱导细胞死亡。不幸的是，神经胶质瘤细胞经常对TMZ治疗产生抗性，MGMT启动子的DNA去甲基化被确定为主要原因。然而，在TMZ诱导的细胞凋亡中，通常保护细胞免受细胞毒性应激的蛋白质的贡献尚未得到广泛研究。在这里，我们发现，增加人LN 18和LN 229神经胶质瘤细胞中的差距连接蛋白Cx43的水平增强了对TMZ处理的抗性，而敲低这些相同细胞中的Cx43使它们对TMZ处理敏感。通过表达一个通道死亡或C-末端截短突变体的Cx43，我们表明，Cx43介导的TMZ抗性涉及通道依赖性和独立的功能。通过Annexin V染色确定，LN 229细胞中Cx43的表达减少TMZ诱导的细胞凋亡。Cx43介导的化学抗性似乎通过线粒体凋亡途径起作用，如Bax/Bcl-2比率的降低和细胞色素C的释放所示。我们的研究结果强调了导致TMZ耐药的其他机制和蛋白质，并提高了通过靶向Cx43蛋白提高TMZ效率的可能性。(C)2013由Elsevier Ltd.出版
Glioblastoma multiforme (GBM) is the most aggressive astrocytoma, and therapeutic options are generally limited to surgical resection, radiotherapy, and Temozolomide (TMZ) chemotherapy. TMZ is a DNA alkylating agent that causes DNA damage and induces cell death. Unfortunately, glioma cells often develop resistance to TMZ treatment, with DNA de-methylation of the MGMT promoter identified as the primary reason. However, the contributions from proteins that normally protect cells against cytotoxic stress in TMZ-induced apoptosis have not been extensively explored. Here, we showed that increasing the level of the gap junction protein, Cx43, in human LN18 and LN229 glioma cells enhances resistance to TMZ treatment while knockdown of Cx43 in these same cells sensitizes them to TMZ treatment. By expressing a channel-dead or a C-terminal truncation mutant of Cx43, we show that Cx43-mediated TMZ resistance involves both channel dependent and independent functions. Expression of Cx43 in LN229 cells decreases TMZ-induced apoptosis, as determined by Annexin V staining. Cx43-mediated chemoresistance appears to be acting via a mitochondrial apoptosis pathway as manifested by the reduction in Bax/Bcl-2 ratio and the release of cytochrome C. Our findings highlight additional mechanisms and proteins that contribute to TMZ resistance, and raise the possibility of increasing TMZ efficiency by targeting Cx43 protein.This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap junction Channels and Hemichannels'. (C) 2013 Published by Elsevier Ltd.