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

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.

Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract

“…The mechanism and the role of polyamines in the regulation of NOS2 expression are unknown and should be addressed in further studies. A compensatory increase in intestinal but not colonic NOS3 expression in the absence of NOS2 was observed as reported previously by us (25). NOS3 was mainly localized to the nucleus and cytoplasmic expression was low in NOS2 knockout mice (25).…”

“…A compensatory increase in intestinal but not colonic NOS3 expression in the absence of NOS2 was observed as reported previously by us (25). NOS3 was mainly localized to the nucleus and cytoplasmic expression was low in NOS2 knockout mice (25). Because of this cellular distribution, polyamine uptake was likely not influenced by NOS3.…”

Effect of arginine on angiogenesis induced by human colon cancer: in vitro and in vivo studies

“…This result was similar to a report by Scott et al [35] that iNOS plays an antineoplastic role in a mouse model of familial adenomatous polyposis. However, our study was inconsistent with a previous report by Yerushalmi et al [36], who found that iNO derived from Arg promotes colonic tumorigenesis in congenital multiple intestinal neoplastic mice. The contradictory results related to iNOS involvement in colonic carcinogenesis may have resulted from different animal models.…”

“…The contradictory results related to iNOS involvement in colonic carcinogenesis may have resulted from different animal models. In their experiment, elevated dietary Arg increased colonic NO and peroxynitrite concentrations, which can cause DNA damage resulting in mutagenesis and tumor initiation [36]. In our study, dietary Arg supplementation may have resulted in endogenous NO production by tumor cells and host cells, which may consequently have reduced tumor progression.…”

Endoscopic optical coherence tomography and laser-induced fluorescence spectroscopy in a murine colon cancer model

“…We believe the mice that died prior to study completion suffered from excessive adenoma burden of the small intestine. In future studies, we will incorporate treatments, such as arginine-enriched diets, to encourage lower rather than upper GI disease [16]. Because of the small amount of disease analyzed, additional studies must be performed to confirm these preliminary results.…”