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Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress

Caitlin E Tolbert1, Matthew V Beck2, Claire E Kilmer3

  • 1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.

Biochemical and Biophysical Research Communications
|December 17, 2018
PubMed

Insights

Loss of ATM kinase activity increases oxidative stress and activates Rac1, promoting cancer cell migration. Restoring ROS levels or inhibiting Rac1 normalizes this pro-migratory behavior.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Ataxia-telangiectasia mutated (ATM) kinase is crucial for DNA double-strand break repair.
  • ATM deficiency is linked to increased tumor development, migration, and invasion.
  • ATM-deficient cells exhibit elevated oxidative stress, but its role in cancer is unclear.

Purpose of the Study:

  • To investigate the mechanism linking ATM deficiency, oxidative stress, and cancer cell migration.
  • To explore the role of Rac1 activation in ATM-deficient cells.

Main Methods:

  • Assessing intracellular reactive oxygen species (ROS) levels in ATM-deficient cells.
  • Measuring Rac1 activation and its downstream effects on cytoskeletal rearrangements.
  • Utilizing Rac1 siRNA and ROS scavengers (N-Acetyl-L-cysteine) to evaluate migratory behavior.

Main Results:

  • Loss of ATM kinase activity leads to increased intracellular ROS.
  • Elevated ROS directly activates Rac1, independent of canonical pathways.
  • Activated Rac1 promotes cytoskeletal changes, enhancing cellular spreading and motility.
  • Inhibition of Rac1 or ROS scavenging restores normal cell migration.

Conclusions:

  • ATM activity regulates Rac1 activation through ROS generation.
  • This novel pathway links ATM status to pro-migratory cancer cell behavior.
  • Targeting the ATM-ROS-Rac1 axis may offer therapeutic strategies for cancer treatment.
Keywords:
ATMMigrationRac1Reactive oxygen species

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