title: MutL homolog 1 contributes to temozolomide-induced autophagy via ataxia-telangiectasia mutated in glioma.
abstract: In the present study, mutL homolog 1 (MLH1) small interfering (si)RNA, KU‑55933, an ataxia‑telangiectasia mutated (ATM) inhibitor, and compound C, an adenosine monophosphate‑activated protein kinase (AMPK) inhibitor, were used to investigate the mechanisms underlying temozolomide (TMZ)‑induced autophagy and to determine the role of MLH1 and ATM in autophagy. MLH1 siRNA and KU‑55933 inhibited the phosphorylation of AMPK and ULK1 and reduced the levels of autophagy. MLH1 siRNA inhibited the phosphorylation of ATM and attenuated TMZ cytotoxicity, whereas the inhibition of ATM‑AMPK augmented TMZ cytotoxicity in inherently TMZ‑sensitive glioma cells. Therefore, TMZ induced autophagy via the ATM‑AMPK pathways and the activation of ATM‑AMPK was MLH1‑dependent. The inhibition of ATM‑AMPK enhanced TMZ cytotoxicity in inherently TMZ‑sensitive glioma cells.
authors: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors: Yuhui
authors: Y
authors: Zou
authors: Department of Medical Information, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors: Qiong
authors: Q
authors: Wang
authors: Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.
authors: Weimin
authors: W
authors: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005910:Glioma; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000077204:Temozolomide
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D047908:Intracellular Signaling Peptides and Proteins; C501486:MLH1 protein, human; D009025:Morpholines; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D034741:RNA, Small Interfering; 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; D000070957:MutL Protein Homolog 1; D000077204:Temozolomide