Activation of AMP-activated Protein Kinase by Temozolomide Contributes to Apoptosis in Glioblastoma Cells via p53 Activation and mTORC1 Inhibition
Activation of AMP-activated Protein Kinase by Temozolomide Contributes to Apoptosis in Glioblastoma Cells via p53 Activation and mTORC1 Inhibition
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替莫唑胺激活 AMP 激活蛋白激酶，通过 p53 激活和 mTORC1 抑制促进胶质母细胞瘤细胞凋亡
DOI：
10.1074/jbc.m110.164046
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发表时间：
2010-12-24
影响因子：
4.8
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Zhang, Wen-bin;Wang, Zhuo;Yang, Yong
甲基化药物如替莫唑胺（TMZ）被广泛用于治疗包括恶性胶质母细胞瘤在内的脑肿瘤。然而，tmz诱导胶质母细胞瘤细胞死亡和凋亡的机制尚不完全清楚。在这里，我们测试了amp活化蛋白激酶（AMPK）在这一过程中的潜在参与。我们发现甲基化剂TMZ和n -甲基-n '-硝基-n -亚硝基胍可诱导原代培养的人胶质母细胞瘤和胶质母细胞瘤细胞系AMPK活化。tmz诱导的o -6-甲基鸟嘌呤的产生参与了AMPK的激活。o -6-苄基鸟嘌呤是一种o -6-甲基鸟嘌呤- dna甲基转移酶抑制剂，它可以增强tmz诱导的o -6-甲基鸟嘌呤的产生，从而增强活性氧的产生，这是AMPK激活的上游信号。AMPK的激活参与了tmz诱导的胶质母细胞瘤细胞死亡和凋亡。AMPK抑制剂（化合物C）或AMPK α siRNA敲低可抑制tmz诱导的胶质母细胞瘤细胞死亡和凋亡，而AMPK激活剂5-氨基咪唑-4-羧酰胺-1- β - d -核呋喃苷可增强这种作用。在进一步的研究中，我们发现AMPK的激活参与了tmz诱导的p53激活以及随后的p21、Noxa和Bax的上调。TMZ激活AMPK还可抑制mTOR复合物1 （mTORC1）信号传导，促进抗凋亡蛋白Bcl-2下调，共同介导TMZ诱导的促细胞凋亡作用。我们的研究表明，TMZ激活AMPK有助于胶质母细胞瘤细胞凋亡，可能是通过促进p53激活和抑制mTORC1信号传导。
Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumors including malignant glioblastoma. The mechanism of TMZ-induced glioblastoma cell death and apoptosis, however, is not fully understood. Here, we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found that methylating agents TMZ and N-methyl-N'-nitro-N-nitrosoguanidine induce AMPK activation in primary cultured human glioblastoma and glioblastoma cell lines. TMZ-induced O-6-methylguanine production is involved in AMPK activation. O-6-benzylguanine, an O-6-methylguanine-DNA methyltransferase inhibitor, enhances TMZ-induced O-6-methylguanine production, leading to enhanced reactive oxygen species production, which serves as an upstream signal for AMPK activation. Activation of AMPK is involved in TMZ-induced glioblastoma cell death and apoptosis. AMPK inhibitor (Compound C) or AMPK alpha siRNA knockdown inhibits TMZ-induced glioblastoma cell death and apoptosis, whereas AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside enhances it. In further studies, we found that activation of AMPK is involved in TMZ-induced p53 activation and subsequent p21, Noxa, and Bax up-regulation. Activation of AMPK by TMZ also inhibits mTOR complex 1 (mTORC1) signaling and promotes anti-apoptosis protein Bcl-2 down-regulation, which together mediate TMZ-induced pro-cell apoptosis effects. Our study suggests that activation of AMPK by TMZ contributes to glioblastoma cell apoptosis, probably by promoting p53 activation and inhibiting mTORC1 signaling.