Direct activation of ATM by resveratrol under oxidizing conditions

• Published in: PloS one 2014-06, Vol.9 (6), p.e97969
• Main Authors: Lee, Ji-Hoon, Guo, Zhi, Myler, Logan R, Zheng, Suting, Paull, Tanya T
• Format: Article
• Language: English
• Subjects: Antioxidants - pharmacology; Apoptosis; Ataxia; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - metabolism; Autophagy; Biology and life sciences; Biotechnology; Bleomycin - pharmacology; Caffeine; Cancer; Cancer therapies; Catalysis; Cell cycle; Cell death; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; HCT116 Cells; HEK293 Cells; Humans; Hydrogen Peroxide - pharmacology; Kinases; Mammalian cells; Molecular biology; Oxidants - pharmacology; Oxidation; Oxidative stress; Oxygen; Phosphorylation; Phosphorylation - drug effects; Protein kinase; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Resveratrol; Rodents; Senescence; Signal transduction; Signal Transduction - drug effects; Signaling; Stilbenes - pharmacology; Substrates; Transformed cells; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0097969

Resveratrol has been widely reported to reduce cancer progression in model systems and to selectively induce cell death in transformed cell lines. Many enzymes have been reported to respond to resveratrol in mammalian cells, including the Ataxia-Telangiectasia Mutated (ATM) protein kinase that acts in DNA damage recognition, signaling, and repair. Here we investigate the responses of ATM to resveratrol exposure in normal and transformed human cell lines and find that ATM autophosphorylation and substrate phosphorylation is stimulated by resveratrol in a manner that is promoted by reactive oxygen species (ROS). We observe direct stimulatory effects of resveratrol on purified ATM in vitro and find that the catalytic efficiency of the kinase on a model substrate is increased by resveratrol. In the purified system we also observe a requirement for oxidation, as the effect of resveratrol on ATM signaling is substantially reduced by agents that prevent disulfide bond formation in ATM. These results demonstrate that resveratrol effects on ATM are direct, and suggest a mechanism by which the oxidizing environment of transformed cells promotes ATM activity and blocks cell proliferation.