The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas.
The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas.
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DOI：
10.18632/oncotarget.17737
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Savaskan N
中科院分区：
文献类型：
--
作者：
Chen D;Rauh M;Buchfelder M;Eyupoglu IY;Savaskan N
恶性神经胶质瘤是一种破坏性肿瘤，治愈性治疗选择有限。替莫唑胺（TMZ，Temcat®，Temodal®或Temodar®）是恶性胶质瘤的一线治疗药物，但耐药性的发展仍然是一个主要问题。活化转录因子4（ATF 4）是胶质瘤中重要的氧化代谢调节因子，其在TMZ耐药发病机制中的作用仍然不清楚。我们研究了TMZ在增强的ATF 4表达（ATF 4 OE）和ATF 4敲低（ATF 4KD）条件下对人脑胶质瘤细胞的作用。我们监测了人胶质瘤中的细胞存活、ATF 4 mRNA表达和xCT（SLC 7a 11）调节。TMZ处理诱导转录应答，其中ATF 4、xCT和Nrf 2的表达升高，作为ER应激和毒性细胞损伤应答的标志。ATF 4过表达（ATF 4 OE）促进人类胶质瘤中的TMZ抗性并抑制TMZ诱导的自噬。相反，与野生型胶质瘤相比，小干扰RNA（ATF 4KD）对ATF 4的抑制导致TMZ易感性和自噬增加。ATF 4 OE胶质瘤显示细胞周期移位和凋亡细胞死亡减少，而ATF 4KD胶质瘤显示对细胞周期重排的更高易感性。因此，ATF 4 OE神经胶质瘤细胞的迁移能力几乎不受TMZ处理的影响。相比之下，ATF 4KD神经胶质瘤在TMZ应用后显示迁移停止。从机制上讲，xCT升高是ATF 4激活的结果，xCT水平升高会放大ATF 4诱导的TMZ耐药性。我们的数据表明，在胶质瘤中，ATF 4作为一个化疗耐药基因发挥作用，其促肿瘤作用主要由其转录靶点xCT决定。因此，ATF 4的治疗性失活可能是克服人类胶质瘤中的化学抗性和促进药物疗效的有前景的策略。
Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat®, Temodal® or Temodar®) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4OE) and ATF4 knock down (ATF4KD). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4OE) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4KD) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4OE gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4KD gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4OE glioma cells is almost not affected by TMZ treatment. In contrast, ATF4KD gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
影响因子：
11.2
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Tsuchihashi K;Okazaki S;Ohmura M;Ishikawa M;Sampetrean O;Onishi N;Wakimoto H;Yoshikawa M;Seishima R;Iwasaki Y;Morikawa T;Abe S;Takao A;Shimizu M;Masuko T;Nagane M;Furnari FB;Akiyama T;Suematsu M;Baba E;Akashi K;Saya H;Nagano O
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Nagano O
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
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Ron, D
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8
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Savaskan, N. E.;Seufert, S.;Hahnen, E.
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Hahnen, E.
影响因子：
5.3
作者：
Blais, JD;Filipenko, V;Bell, JC
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Bell, JC