Contribution of ATM and ATR to the Resistance of Glioblastoma and Malignant Melanoma Cells to the Methylating Anticancer Drug Temozolomide
Contribution of ATM and ATR to the Resistance of Glioblastoma and Malignant Melanoma Cells to the Methylating Anticancer Drug Temozolomide
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DOI：
10.1158/1535-7163.mct-13-0136
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发表时间：
2013-11-01
影响因子：
5.7
通讯作者：
Kaina, Bernd
中科院分区：
文献类型：
--
作者：
Eich, Marcus;Roos, Wynand Paul;Kaina, Bernd
替莫唑胺和其他甲基化药物在恶性胶质瘤和转移性黑色素瘤治疗中诱导的主要细胞毒DNA加合物是O-6-甲基鸟嘌呤(O-6-Meg)。这种初级DNA损伤通过错配修复转化为继发性损伤，后者阻止复制，进而诱导DNA双链断裂，从而触发DNA损伤反应(DDR)。DDR的关键上游成员是磷脂酰肌醇3-激酶、共济失调、毛细血管扩张突变(ATM)和共济失调、毛细血管扩张和RAD3相关(ATR)。在这里，我们讨论了ATM和ATR在替莫唑胺后细胞死亡反应中的重要性的问题。我们发现：(I)ATM和ATR突变的细胞对替莫唑胺高度敏感，(Ii)O-6-Meg触发了ATM和ATR的激活，(Iii)ATM和ATR的敲除增强了胶质母细胞瘤和恶性黑色素瘤细胞的杀伤，其中ATR敲除细胞的作用更强和显著，(Iv)ATR而不是ATM，敲除了胶质瘤细胞中的H2 AX，CHK1和Chk2的磷酸化，以及(V)药物抑制CHK1比CHK2更显著地增强了替莫唑胺诱导的细胞死亡。这些数据表明，ATM和更好的ATR抑制是一种有用的策略，可以使癌细胞对替莫唑胺以及其他抗癌药物敏感。(C)2013年AACR。
The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in malignant glioma and metastasized melanoma therapy is O-6-methylguanine (O-6-MeG). This primary DNA damage is converted by mismatch repair into secondary lesions, which block replication and in turn induce DNA double-strand breaks that trigger the DNA damage response (DDR). Key upstream players in the DDR are the phosphoinositide 3-kinases ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR). Here, we addressed the question of the importance of ATM and ATR in the cell death response following temozolomide. We show that (i) ATM- and ATR-mutated cells are hypersensitive to temozolomide, (ii) O-6-MeG triggers ATM and ATR activation, (iii) knockdown of ATM and ATR enhances cell kill in gliobalstoma and malignant melanoma cells with a stronger and significant effect in ATR knockdown cells, (iv) ATR, but not ATM, knockdown abolished phosphorylation of H2AX, CHK1, and CHK2 in glioma cells, and (v) temozolomide-induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2. The data suggest that ATM and, even better, ATR inhibition is a useful strategy in sensitizing cancer cells to temozolomide and presumably also other anticancer drugs. (C) 2013 AACR.