Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells.
Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells.
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DOI：
10.5732/cjc.012.10236
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发表时间：
2014-02
影响因子：
--
通讯作者：
Chen ZP
中科院分区：
文献类型：
--
作者：
Qiu ZK;Shen D;Chen YS;Yang QY;Guo CC;Feng BH;Chen ZP
O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）可以去除DNA烷基化加合物，从而修复受损的DNA并有助于胶质瘤对烷化剂的耐药性。此外，神经胶质瘤干细胞样细胞（GSC）已被证明参与神经胶质瘤的复发和治疗耐药。在本研究中，我们旨在研究 GSC 中 MGMT 的表达和调节机制，以及 MGMT 与替莫唑胺 (TMZ) 敏感性的关系。通过无血清克隆培养，从一种 MGMT 阳性细胞系 (SF-767) 和 7 种 MGMT 阴性细胞系（U251、SKMG-4、SKMG-1、SF295、U87、MGR1 和 MGR2）中富集 GSC。来自 U251G、SKMG-4G、SF295G 和 SKMG-1G 细胞系的 GSC 变为 MGMT 阳性，但来自 U87G、MGR1G 和 MGR2G 细胞系的 GSC 仍保持 MGMT 阴性。然而，所有 GSC 及其亲本神经胶质瘤细胞系均呈核因子-κB (NF-κB) 阳性。此外，GSC 比其亲代神经胶质瘤细胞系对 TMZ 具有更强的耐药性（P < 0.05）。然而，MGMT阳性和MGMT阴性GSC之间TMZ的50%抑制浓度（IC50）无显着差异（P > 0.05）。当我们用 TMZ 加 MG-132（一种 NF-κB 抑制剂）处理 MGMT 阳性 GSC 时，与单独用 TMZ 处理的 GSC 相比，抗肿瘤活性显着增强（P < 0.05）。此外，我们发现 MGMT 表达通过 MG-132 下调 NF-κB 表达而降低。我们的结果表明，MG-132 可能抑制 NF-κB 表达并进一步降低 MGMT 表达，从而对 MGMT 阳性 GSC 产生协同作用。这些结果表明，MGMT 表达增强有助于 MGMT 阳性 GSC 中的 TMZ 耐药。
O6-methylguanine DNA methyltransferase (MGMT) can remove DNA alkylation adducts, thereby repairing damaged DNA and contributing to the drug resistance of gliomas to alkylating agents. In addition, glioma stem-like cells (GSCs) have been demonstrated to be involved in the recurrence and treatment resistance of gliomas. In this study, we aimed to investigate MGMT expression and regulatory mechanisms in GSCs and the association of MGMT with temozolomide (TMZ) sensitivity. GSCs were enriched from one MGMT-positive cell line (SF-767) and 7 MGMT-negative cell lines (U251, SKMG-4, SKMG-1, SF295, U87, MGR1, and MGR2) through serum-free clone culture. GSCs from the U251G, SKMG-4G, SF295G, and SKMG-1G cell lines became MGMT-positive, but those from the U87G, MGR1G, and MGR2G cell lines remained MGMT-negative. However, all the GSCs and their parental glioma cell lines were positive for nuclear factor-κB (NF-κB). In addition, GSCs were more resistant to TMZ than their parental glioma cell lines (P < 0.05). However, there was no significant difference in the 50% inhibition concentration (IC50) of TMZ between MGMT-positive and MGMT-negative GSCs (P > 0.05). When we treated the MGMT-positive GSCs with TMZ plus MG-132 (an NF-κB inhibitor), the antitumor activity was significantly enhanced compared to that of GSCs treated with TMZ alone (P < 0.05). Furthermore, we found that MGMT expression decreased through the down-regulation of NF-κB expression by MG-132. Our results show that MG-132 may inhibit NF-κB expression and further decrease MGMT expression, resulting in a synergistic effect on MGMT-positive GSCs. These results indicate that enhanced MGMT expression contributes to TMZ resistance in MGMT-positive GSCs.
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影响因子：
158.5
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