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, KU­55933, an ataxia­telangiectasia mutated (ATM) inhibitor, and compound C, an adenosine monophosphate­activated 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 KU­55933 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 ATM­AMPK augmented TMZ cytotoxicity in inherently TMZ­sensitive glioma cells. Therefore, TMZ induced autophagy via the ATM­AMPK pathways and the activation of ATM­AMPK was MLH1­dependent. The inhibition of ATM­AMPK enhanced TMZ cytotoxicity in inherently TMZ­sensitive glioma cells.