Hypochlorous acid activates the tumor suppressor protein p53 in cultured human skin fibroblasts.
The carcinogenicity associated with chronic inflammation has been attributed to neutrophils and the oxidants they produce. Neutrophils accumulate at sites of chronic inflammation, where they are stimulated to produce hydrogen peroxide which is converted to hypochlorous acid by coreleased myeloperoxidase. We report here that levels of the tumor suppressor protein p53 were increased in cultured human skin fibroblasts that had been incubated with stimulated neutrophils. The increase in p53 required the myeloperoxidase-dependent generation of hypochlorous acid and could be mimicked by exposing cells to a flux of hypochlorous acid produced by purified myeloperoxidase and a hydrogen peroxide-generating system. Levels of p53 were very sensitive to hypochlorous acid, with fluxes as low as 0.2 microM per min being effective. Levels of the p53-dependent protein WAF1/CIP1 were also elevated when fibroblasts were treated with hypochlorous acid. This result indicates that the p53 in the cells treated with hypochlorous acid was transcriptionally active. Hydrogen peroxide alone also elevated p53 and WAF1/CIP1, but the fluxes required were nearly 10-fold higher than those that were effective for hypochlorous acid. Our results implicate hypochlorous acid in the neutrophil-dependent initiation of a signal transduction pathway which could minimize the carcinogenicity of chronic inflammation.
Vile
G F
GF
Department of Pathology, Christchurch School of Medicine, Christchurch, New Zealand. gvile@chmeds.ac.nz
Rothwell
L A
LA
Kettle
A J
AJ
D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018375:Neutrophil Activation / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D012867:Skin / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D006997:Hypochlorous Acid; D009195:Peroxidase