Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.003
Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation
Mihwa Hwang, Dong Wha Jun, Bo Ram Song, Hanna Shim, Chang-Hun Lee and Sunshin Kim*
Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
*E-mail: ksunshin@ncc.re.kr
Tel: +82-31-920-2205, Fax: +82-31-920-2006
Received: January 7, 2023; Revised: February 15, 2023; Accepted: February 22, 2023; Published online: March 21, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: ATM, Autophagy, Autolysosome, Combination therapy, Cancer therapy

This Article


Cited By Articles
  • CrossRef (0)

e-submission

Archives