title: Temozolomide induces autophagy via ATM‑AMPK‑ULK1 pathways in glioma.
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.
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Medical Information, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Bingling
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077204:Temozolomide
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018906:Antineoplastic Agents, Alkylating; D047908:Intracellular Signaling Peptides and Proteins; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D011753:Pyrones; D003606:Dacarbazine; D064007:Ataxia Telangiectasia Mutated Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases; D000077204:Temozolomide