The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis

Hagit F. Yerushalmi, David G. Besselsen, Natalia Ignatenko, Karen A. Blohm-Mangone, Jose L. Padilla-Torres, David E. Stringer, Haiyan Cui, Hana Holubec, Claire M. Payne, Eugene W. Gerner

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Abstract

Arginine is catabolized by NOS2 and other nitric oxide synthases to form nitric oxide. We evaluated the roles of dietary arginine and Nos2 in Apc-dependent intestinal tumorigenesis in Min mice with and without a functional Nos2 gene. NOS2 protein was expressed only in intestinal tissues of Apc Min/+ Nos2+/+ mice. NOS3 expression was higher in intestinal tissues of mice lacking Nos2, mainly in the small intestine. When diet was supplemented with arginine (0.2% and 2% in drinking water), lack of Nos2 results in decreased tumorigenesis in both small intestine and colon. In Nos2 knockout mice, supplemental arginine (up to 2%) caused a decrease in small intestinal tumor number and size. The arginine-dependent decrease was associated with an increase in nitrotyrosine formation and apoptosis in the region of intestinal stem cells. Mice expressing Nos2 did not show these changes. These mice did, however, show an arginine-dependent increase in colon tumor number and incidence, while no effect on apoptosis was seen. These changes were associated with increased nitrotyrosine formation in epithelial cells. Mice lacking Nos2 did not show changes in tumorigenesis or nitrotyrosine formation, while demonstrating an arginine-dependent increase in apoptosis. These data suggest that Nos2 and dietary arginine have significant effects on intestinal and colonic tumorigenesis in Min mice. In both tissues, loss of Nos2 is associated with decreased tumorigenesis when mice are supplemented with dietary arginine. In the small intestine, Nos2 prevents the arginine-induced decrease in tumor number and size, which is associated with NOS3 expression and increased apoptosis. In the colon, Nos2 is required for the arginine-induced increase in tumor number and incidence.

Original languageEnglish (US)
Pages (from-to)93-105
Number of pages13
JournalMolecular Carcinogenesis
Volume45
Issue number2
DOIs
StatePublished - Feb 2006

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Nitric Oxide Synthase
Arginine
Carcinogenesis
Apoptosis
Small Intestine
Colon
Neoplasms
Incidence
Knockout Mice
Drinking Water
Nitric Oxide
Stem Cells
Epithelial Cells
Diet

Keywords

  • Arginine
  • Min mice
  • Nos2
  • Nos3

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Yerushalmi, H. F., Besselsen, D. G., Ignatenko, N., Blohm-Mangone, K. A., Padilla-Torres, J. L., Stringer, D. E., ... Gerner, E. W. (2006). The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis. Molecular Carcinogenesis, 45(2), 93-105. https://doi.org/10.1002/mc.20168

The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis. / Yerushalmi, Hagit F.; Besselsen, David G.; Ignatenko, Natalia; Blohm-Mangone, Karen A.; Padilla-Torres, Jose L.; Stringer, David E.; Cui, Haiyan; Holubec, Hana; Payne, Claire M.; Gerner, Eugene W.

In: Molecular Carcinogenesis, Vol. 45, No. 2, 02.2006, p. 93-105.

Research output: Contribution to journalArticle

Yerushalmi, HF, Besselsen, DG, Ignatenko, N, Blohm-Mangone, KA, Padilla-Torres, JL, Stringer, DE, Cui, H, Holubec, H, Payne, CM & Gerner, EW 2006, 'The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis', Molecular Carcinogenesis, vol. 45, no. 2, pp. 93-105. https://doi.org/10.1002/mc.20168
Yerushalmi HF, Besselsen DG, Ignatenko N, Blohm-Mangone KA, Padilla-Torres JL, Stringer DE et al. The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis. Molecular Carcinogenesis. 2006 Feb;45(2):93-105. https://doi.org/10.1002/mc.20168
Yerushalmi, Hagit F. ; Besselsen, David G. ; Ignatenko, Natalia ; Blohm-Mangone, Karen A. ; Padilla-Torres, Jose L. ; Stringer, David E. ; Cui, Haiyan ; Holubec, Hana ; Payne, Claire M. ; Gerner, Eugene W. / The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis. In: Molecular Carcinogenesis. 2006 ; Vol. 45, No. 2. pp. 93-105.
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