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Temozolomide induces autophagy via ATM‑AMPK‑ULK1 pathways in glioma

Yuhui Zou1, Qiong Wang2, Bingling Li3

  • 1Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China.

Molecular Medicine Reports
|April 17, 2014
PubMed

Insights

Temozolomide (TMZ) induces autophagy through ATM-AMPK-ULK1 pathways, promoting glioma chemoresistance. Inhibiting autophagy, particularly AMPK, enhances TMZ

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Autophagy is a cellular process that can lead to chemoresistance in glioma following temozolomide (TMZ) treatment.
  • The precise molecular mechanisms by which TMZ triggers autophagy remain largely unelucidated.

Purpose of the Study:

  • To investigate the molecular pathways of TMZ-induced autophagy in glioma.
  • To assess the impact of autophagy inhibition on TMZ's cytotoxicity.

Main Methods:

  • Utilized ATM inhibitor KU-55933 and AMPK inhibitor compound C in U87MG and U251 glioma cell lines.
  • Monitored autophagy markers such as LC3B cleavage and acidic vesicular organelle formation.
  • Evaluated cell viability, DNA double-strand breaks (γH2AX), and apoptosis.

Main Results:

  • Both KU-55933 and compound C inhibited autophagy initiation kinase ULK1, decreasing autophagy.
  • AMPK-ULK1 activation was dependent on ATM.
  • Autophagy inhibition using compound C enhanced TMZ cytotoxicity, increasing DNA damage and apoptosis.

Conclusions:

  • TMZ induces autophagy via the ATM-AMPK-ULK1 signaling cascade.
  • Targeting AMPK may overcome TMZ chemoresistance in glioma, especially in O6-methylguanine DNA methyltransferase-negative tumors.

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