title: Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells.
abstract: 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.
authors: State Key Laboratory of Oncology in South China; Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China. chenzhp@sysucc.org.cn.
authors: Zhi-Kun
authors: ZK
authors: Qiu
authors: Dong
authors: D
authors: Shen
authors: Yin-Sheng
authors: YS
authors: Chen
authors: Qun-Ying
authors: QY
authors: Yang
authors: Cheng-Cheng
authors: CC
authors: Guo
authors: Bing-Hong
authors: BH
authors: Feng
authors: Zhong-Ping
authors: ZP
authors: Chen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007976:Leupeptins; D016328:NF-kappa B; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000077204:Temozolomide
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