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Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation

Mihwa Hwang1, Dong Wha Jun1, Bo Ram Song1

  • 1Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.

Biomolecules & Therapeutics
|March 20, 2023
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) inhibitors disrupt autophagy by blocking autolysosome formation, leading to cell death. This finding expands the potential use of ATM inhibitors in cancer therapy.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Ataxia-telangiectasia mutated (ATM) is a key kinase in the DNA damage response (DDR), crucial for signaling after DNA double-strand breaks (DSBs).
  • ATM inhibitors are explored for cancer therapy to enhance DNA damage-induced cytotoxicity.
  • ATM also plays a role in autophagy, a cellular process for maintaining homeostasis.

Purpose of the Study:

  • To investigate the role of ATM in autophagy.
  • To determine the effect of ATM inhibitors on autophagic flux and cell viability.

Main Methods:

  • Utilized ATM inhibitors (KU-55933, KU-60019) in various cell lines.
  • Assessed autophagosome and autolysosome formation.
  • Examined the impact of ATM knockdown via siRNA on autophagy and cell death.

Main Results:

  • ATM inhibitors caused autophagosome accumulation and impaired autolysosome formation.
  • Excessive autophagosome buildup and cell death were observed under autophagy-inducing conditions with ATM inhibitors.
  • ATM inhibition via siRNA also blocked autophagic flux and induced cell death.

Conclusions:

  • ATM is implicated in the regulation of autolysosome formation.
  • ATM inhibitors may offer expanded therapeutic applications in cancer treatment by modulating autophagy.
Keywords:
ATMAutolysosomeAutophagyCancer therapyCombination therapy

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