Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation

  • Mihwa Hwang (Research Institute, National Cancer Center) ;
  • Dong Wha Jun (Research Institute, National Cancer Center) ;
  • Bo Ram Song (Research Institute, National Cancer Center) ;
  • Hanna Shim (Research Institute, National Cancer Center) ;
  • Chang-Hun Lee (Research Institute, National Cancer Center) ;
  • Sunshin Kim (Research Institute, National Cancer Center)
  • Received : 2023.01.07
  • Accepted : 2023.02.22
  • Published : 2023.09.01
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Abstract

Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles. In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation. Under autophagy-inducing conditions, the ATM inhibitors caused excessive autophagosome accumulation and cell death. This new function of ATM in autophagy was also observed in numerous cell lines. Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions. Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (NRF-2018R1D1A1B07046570), Ministry of Health & Welfare of Korea (HI21C0416) ,and National Cancer Center Grant (1710352 and 2210552). This study was also supported by the Research Core Center (Proteomics Core Team and Microscopy Core Team) of the National Cancer Center Korea. We thank Dr. Kyung-Hee Kim and Ms. Mi-ae Kim for technical support.

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