The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis.
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.
Yerushalmi
Hagit F
HF
Gastrointestinal Cancer Program, Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.
Besselsen
David G
DG
Ignatenko
Natalia A
NA
Blohm-Mangone
Karen A
KA
Padilla-Torres
Jose L
JL
Stringer
David E
DE
Cui
Haiyan
H
Holubec
Hana
H
Payne
Claire M
CM
Gerner
Eugene W
EW
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D005260:Female; D007414:Intestinal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C002744:3-nitrotyrosine; D014443:Tyrosine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III