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cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Rui Wang1, Bianca N Islam1, Allison Bridges1

  • 1Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia.

The American Journal of Pathology
|December 22, 2016
PubMed

Insights

Cyclic guanosine monophosphate (cGMP) and protein kinase G2 (PKG2) activate the tumor suppressor FoxO in colon cells. This pathway, enhanced by PDE5 inhibitors like vardenafil, reduces oxidative stress and improves barrier integrity, offering therapeutic potential for colon cancer.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Oncology

Background:

  • Cyclic guanosine monophosphate (cGMP) signaling is crucial for colon health, potentially suppressing colitis and colon cancer.
  • Forkhead box O (FoxO) transcription factors are key regulators of cellular stress responses and tumor suppression.

Purpose of the Study:

  • To investigate the role of cGMP and type 2 cGMP-dependent protein kinase (PKG2) in activating FoxO in colon cancer cells and mouse colon epithelium.
  • To explore the therapeutic potential of targeting the cGMP/PKG2/FoxO pathway in colon diseases.

Main Methods:

  • Activation of PKG2 in colon cancer cells and treatment of colon explants with 8Br-cGMP.
  • Analysis of FoxO activation, target gene expression, and epithelial redox stress in wild-type and Prkg2 knockout mice.
  • Administration of vardenafil (a PDE5 inhibitor) to mice and treatment of human colonic biopsy specimens with 8Br-cGMP.

Main Results:

  • PKG2 activation in colon cancer cells inhibited proliferation and activated FoxO.
  • 8Br-cGMP treatment activated FoxO target genes and reduced epithelial redox stress in explants.
  • Vardenafil treatment in mice increased nuclear FoxO3a, upregulated FoxO target genes, reduced redox stress, and enhanced epithelial barrier integrity.
  • 8Br-cGMP activated FoxO target genes (catalase, SOD) in human colon biopsies, indicating conserved signaling.

Conclusions:

  • A novel cGMP/PKG2/FoxO signaling pathway in the colon epithelium protects against redox stress.
  • FoxO tumor suppressors are activated by this pathway, which is regulated by endogenous cGMP/PKG2.
  • Phosphodiesterase-5 (PDE5) inhibitors represent a potential therapeutic strategy for targeting this pathway in colon diseases.

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