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

Rui Wang, Bianca N. Islam, Allison Bridges, Sarah K. Sharman, Muhan Hu, Yali Hou, Payaningal R. Somanath, Laine Venable, Nagendra Singh, Sangmi Kim, Subbaramiah Sridhar, Franz Hofmann, Darren D Browning

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Signaling through cGMP has therapeutic potential in the colon, where it has been implicated in the suppression of colitis and colon cancer. In this study, we tested the ability of cGMP and type 2 cGMP-dependent protein kinase (PKG2) to activate forkhead box O (FoxO) in colon cancer cells and in the colon epithelium of mice. We show that activation of PKG2 in colon cancer cells inhibited cell proliferation, inhibited AKT, and activated FoxO. Treatment of colon explants with 8Br-cGMP also activated FoxO target gene expression at both RNA and protein levels, and reduced epithelial reduction-oxidation (redox) stress. FoxO3a was the most prominent isoform in the distal colon epithelium, with prominent luminal staining. FoxO3a levels were reduced in Prkg2−/− animals, and FoxO target genes were unaffected by 8Br-cGMP challenge in vitro. Treatment of mice with the phosphodiesterase-5 inhibitor vardenafil (Levitra) mobilized FoxO3a to the nucleus of luminal epithelial cells, which corresponded to increased FoxO target gene expression, reduced redox stress, and increased epithelial barrier integrity. Treatment of human colonic biopsy specimens with 8Br-cGMP also activated catalase and manganese superoxide dismutase expression, indicating that this pathway is conserved in humans. Taken together, these results identify a novel signaling pathway in the colon epithelium, where FoxO tumor suppressors could provide protection from redox stress. Moreover, this pathway is regulated by endogenous cGMP/PKG2 signaling, and can be targeted using phosphodiesterase-5 inhibitors.

Original languageEnglish (US)
Pages (from-to)377-389
Number of pages13
JournalAmerican Journal of Pathology
Volume187
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Colon
Epithelium
Antioxidants
Gene Expression
Colonic Neoplasms
Phosphodiesterase 5 Inhibitors
Cyclic GMP-Dependent Protein Kinase Type II
Colitis
Catalase
Superoxide Dismutase
Protein Isoforms
Epithelial Cells
Cell Proliferation
RNA
Staining and Labeling
Biopsy
Genes
Neoplasms
Proteins
Vardenafil Dihydrochloride

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium. / Wang, Rui; Islam, Bianca N.; Bridges, Allison; Sharman, Sarah K.; Hu, Muhan; Hou, Yali; Somanath, Payaningal R.; Venable, Laine; Singh, Nagendra; Kim, Sangmi; Sridhar, Subbaramiah; Hofmann, Franz; Browning, Darren D.

In: American Journal of Pathology, Vol. 187, No. 2, 01.02.2017, p. 377-389.

Research output: Contribution to journalArticle

Wang, R, Islam, BN, Bridges, A, Sharman, SK, Hu, M, Hou, Y, Somanath, PR, Venable, L, Singh, N, Kim, S, Sridhar, S, Hofmann, F & Browning, DD 2017, 'cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium', American Journal of Pathology, vol. 187, no. 2, pp. 377-389. https://doi.org/10.1016/j.ajpath.2016.10.016
Wang, Rui ; Islam, Bianca N. ; Bridges, Allison ; Sharman, Sarah K. ; Hu, Muhan ; Hou, Yali ; Somanath, Payaningal R. ; Venable, Laine ; Singh, Nagendra ; Kim, Sangmi ; Sridhar, Subbaramiah ; Hofmann, Franz ; Browning, Darren D. / cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium. In: American Journal of Pathology. 2017 ; Vol. 187, No. 2. pp. 377-389.
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