Temozolomide induces autophagy via ATM‑AMPK‑ULK1 pathways in glioma

Zou,Yuhui; Wang,Qiong; Li,Bingling; Xie,Bing; Wang,Weimin

doi:10.3892/mmr.2014.2151

Temozolomide induces autophagy via ATM‑AMPK‑ULK1 pathways in glioma

Authors:
- Yuhui Zou
- Qiong Wang
- Bingling Li
- Bing Xie
- Weimin Wang
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Affiliations: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China, Department of Medical Information, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China, Department of Pharmacy, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China
Published online on: April 15, 2014 https://doi.org/10.3892/mmr.2014.2151
Pages: 411-416

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Abstract

Autophagy is a cytoprotective process, which occurs following temozolomide (TMZ) treatment, and contributes to glioma chemoresistance and TMZ treatment failure. However, the molecular mechanisms by which TMZ induces autophagy are largely unknown. In the current study, the ataxia‑telangiectasia mutated (ATM) inhibitor KU‑55933, adenosine monophosphate‑activated protein kinase (AMPK) inhibitor compound C, and U87MG and U251 cell lines were employed to investigate the molecular mechanisms of TMZ‑induced autophagy in glioma, and to evaluate the effects of autophagy inhibition on TMZ cytotoxicity. KU‑55933 and compound C were observed to inhibit the activation of autophagy‑initiating kinase ULK1 and result in a significant decrease of autophagy as indicated by depressed LC3B cleavage and acidic vesicular organelle formation. The activation of AMPK‑ULK1 was ATM dependent. Autophagy inhibition via the AMPK inhibitor compound C augmented TMZ cytotoxicity as observed by depressed cell viability, increased γH2AX‑marked double‑strand breaks (DSBs) and elevated numbers of apoptotic glioma cells. In conclusion, TMZ induced autophagy via ATM‑AMPK‑ULK1 pathways. TMZ chemoresistance may therefore be overwhelmed by targeting AMPK, particularly for the treatment of O6‑methylguanine DNA methyltransferase‑negative gliomas.

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