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

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... orylation 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. Abbreviations: TMZ, temozolomide; MMR, DNA mismatch repair; MLH1, mutL homolog 1; ATM, ataxia-telangiectasia mutated; AMPK, adenosine monophosphate-activated protein kinase; ULK1, unc-51-like autophagy activating kinase 1