Role of polyamines in arginine‐dependent colon carcinogenesis in Apc^Min/+ mice

Abstract

We evaluated the role of polyamines in arginine-dependent intestinal tumorigenesis in Apc(Min) (/+) mice. Arginine is a substrate for ornithine synthesis and thus can influence polyamine production. Supplementing the diet with arginine increased intestinal and colonic polyamine levels and colonic carcinogenesis. Inhibiting polyamine synthesis with D,L-alpha-diflouromethylornithine (DFMO) decreased small intestinal and colonic polyamine pools. In mice provided basal diet, but not when supplemented with arginine, DFMO decreased small intestinal tumor number and burden, and increased intestinal apoptosis. In mice provided supplemental arginine in the diet, DFMO induced late apoptosis and decreased tumorigenesis in the colon. DFMO slightly reduced tumor incidence, number, and size while significantly decreasing tumor burden and grade. These changes in colon tumorigenesis did not occur in mice not provided supplemental arginine. Our study indicates that polyamines play unique roles in intestinal and colonic carcinogenesis in Apc(Min) (/+) mice. Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model.

Gene expression profiling: Canonical molecular changes and clinicopathological features in sporadic colorectal cancers

“…Expression of the E-cadherin β-catenin was observed in dendritic cells and loss of E-cadherin adhesion trig gered a functionally distinct pathway of maturation linked more closely to the maintenance of tolerance than to the initiation of immunity [23] . In Apc Min/+ mice, in which APC mutations are upregulated, dietary arginine increased colon tumorigenesis [24] . Amongst the eight genes we identified that were associated with APC mutations and Wnt activation, we found that one, PISD, was a novel gene upregulated in tumor cells with these alterations.…”

Pharmacological and dietary agents for colorectal cancer chemoprevention: Effects on polyamine metabolism (Review)

“…In a study by Yerushalmi et al (116), Apc Min/+ mice were fed with arginine concentrations corresponding to the higher range of arginine consumed by humans eating a western style diet. Authors reported that large amounts of arginine in diet increase colonic polyamine levels as well as carcinogenesis.…”

Attenuation of Argininosuccinate Lyase Inhibits Cancer Growth via Cyclin A2 and Nitric Oxide

“…Arginine is also the precursor for many biologic molecules, including polyamines, urea, glutamate, proline, and agmatine (2). Many of these biologic products have been implicated in tumor development, and therefore, feeding mice with arginine enhances tumor growth (5). In contrast, depletion of dietary arginine inhibits liver metastasis (6).…”