MutL homolog 1 contributes to temozolomide-induced autophagy via ataxia-telangiectasia mutated in glioma

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E-ISSN： 1791-3004|11|6|4591-4596

ISSN： 1791-2997

Source： Molecular Medicine Reports, Vol.11, Iss.6, 2015-01, pp. : 4591-4596

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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.