Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells

作者：Li Chun Qi; Kim Min Young; Godoy Luiz C; Thiantanawat Apinya; Trudel Laura J; Wogan Gerald N^*

来源：Proceedings of the National Academy of Sciences, 2009, 106(34): 14547-14551.

DOI：10.1073/pnas.0907539106

• inflammation
• oxidative stress
• reactive nitrogen species
• (S)-nitrosation

The transcription factor NF-E2-related nuclear factor 2 (Nrf2) regulates expression of genes that protect cells from oxidative damage. Here, we characterized nitric oxide (center dot NO)-induced Nrf2-Kelch-like ECH-associated protein 1 (Keap1) signaling and its role in counteracting center dot NO-induced apoptosis of human colon cancer HCT116 cells. Nrf2 was localized in the cytoplasm in control cells; center dot NO triggered its rapid nuclear accumulation, transcriptional activation, and up-regulation of HO-1, NQO1, and GCL, but not GST A4 and P1 subunits. Nrf2 accumulation in the nucleus was also associated with enhanced transcription and posttranscriptional modifications. (S)-nitrosation of Keap1 may contribute to nuclear accumulation of Nrf2 by facilitating its dissociation from Keap1, thus initiating center dot NO-mediated Nrf2 -Keap1 signaling. center dot NO-mediated induction of ARE-dependent genes occurred well before apoptosis, as judged by caspase 3 activation. Collectively, these results show that the Nrf2 -Keap1 signaling pathway mediates protective cellular responses to mitigate center dot NO-induced damage and may contribute to the relative resistance of HCT116 to center dot NO-induced cytotoxicity.

• 出版日期2009-8-25