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Published on: November 17, 2018

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

Chun-Qi Li1, Min Young Kim, Luiz C Godoy

  • 1Department of Biological Engineering and Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 27, 2009
PubMed

Insights

Nitric oxide (*NO) activates the Nrf2-Keap1 pathway, leading to nuclear Nrf2 accumulation and protective gene expression in colon cancer cells. This signaling mitigates *NO-induced apoptosis, enhancing cellular resistance.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of cellular defense against oxidative stress.
  • Nitric oxide (*NO) is a signaling molecule with complex roles in cell physiology and pathology, including cancer.
  • The Nrf2-Keap1 (Kelch-like ECH-associated protein 1) pathway is a critical cellular defense mechanism.

Purpose of the Study:

  • To characterize nitric oxide (*NO)-induced Nrf2-Keap1 signaling in human colon cancer HCT116 cells.
  • To investigate the role of this pathway in counteracting *NO-induced apoptosis.
  • To elucidate the molecular mechanisms underlying *NO-mediated Nrf2 activation.

Main Methods:

  • Characterization of Nrf2 localization and transcriptional activity in response to *NO.
  • Analysis of Nrf2-dependent gene expression (HO-1, NQO1, GCL).
  • Investigation of Keap1 modification, specifically (S)-nitrosation, and its effect on Nrf2-Keap1 interaction.

Main Results:

  • *NO induced rapid nuclear accumulation of Nrf2, leading to transcriptional activation of antioxidant genes like HO-1, NQO1, and GCL.
  • (S)-nitrosation of Keap1 was proposed to facilitate Nrf2 dissociation from Keap1, promoting Nrf2 nuclear translocation.
  • Induction of Nrf2-dependent genes preceded caspase 3 activation, indicating a protective response before the onset of apoptosis.

Conclusions:

  • The Nrf2-Keap1 signaling pathway is activated by *NO in HCT116 cells, mediating protective cellular responses.
  • This pathway mitigates *NO-induced cellular damage and contributes to the relative resistance of HCT116 cells to *NO-induced cytotoxicity.
  • Understanding this mechanism offers potential therapeutic insights for colon cancer treatment.

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