APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse

Abstract

The colorectal mucosa of pre-symptomatic individuals with familial adenomatous polyposis (FAP) contains elevated levels of the proliferation-associated polyamines. The Min mouse, like humans with FAP, expresses an abnormal genotype for the APC tumor suppressor gene. In order to determine how APC mutation influences intestinal tissue polyamine content, we measured steady-state RNA levels of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, antizyme (AZ), a protein which negatively regulates ODC, and the spermidine/spermine N(1)-acetyltransferase (SSAT), the first enzyme in polyamine catabolism. RNA content was increased 6- to 8-fold in both the small intestine and colon for ODC, decreased significantly in the small intestine but not the colon for AZ and was not statistically different in either intestinal tissue for SSAT in Min mice compared with normal littermates. Consistent with the changes in ODC and AZ gene expression, small intestinal, but not colonic, polyamine content was elevated in Min mice compared with normal littermates. Treatment of Min mice with the specific ODC inhibitor difluoromethylornithine (DFMO) suppressed small intestinal, but not colonic, polyamine content and tumor number. These data indicate that small intestinal tissue polyamine content is elevated in Min mice by a mechanism involving APC-dependent changes in ODC and AZ RNA. Further, ODC enzyme activity, which is influenced by both ODC and AZ RNA levels and inhibited by DFMO, is consequential for small intestinal tumorigenesis in this model. In the FAP population, DFMO may be of value in the chemoprevention of small intestinal adenocarcinoma that remains a risk following colectomy.

Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene

“…Furthermore, both ODC RNA and polyamine contents are up-regulated in the intestinal mucosa of mice expressing a mutant APC, compared with normal littermates (17). Intestinal tumorigenesis in these mice is elevated and can be suppressed by treatment with a specific inhibitor of ODC (17).…”

“…Given the suggested role of polyamine levels in APC-dependent intestinal carcinogenesis, as suggested by our studies in mouse and human models (16,17), and because APC has been implicated in the majority of sporadic human colon adenomas and cancers (8), we assessed the relationship between the ODC polymorphism and the risk of adenoma recurrence in participants in a colon cancer prevention trial. We further investigated whether this association was modified by aspirin use.…”

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

“…144 Elevated levels of polyamines and ODC activity have been found in colonic polyps and colon cancer as well as in the min mouse model of familial adenomatous polyposis coli. [145][146][147][148] Treatment of min mice with ␣-difluoromethylornithine (DFMO), a reversible inhibitor of ODC, has been shown to suppress tumorigenesis, suggesting that ODC may be a target for chemopreventive therapies. 148 Inhibitors of ODC have also been found to decrease tumor formation in animal models of bladder, breast, and skin carcinogenesis.…”

“…[145][146][147][148] Treatment of min mice with ␣-difluoromethylornithine (DFMO), a reversible inhibitor of ODC, has been shown to suppress tumorigenesis, suggesting that ODC may be a target for chemopreventive therapies. 148 Inhibitors of ODC have also been found to decrease tumor formation in animal models of bladder, breast, and skin carcinogenesis. 149 -151 DFMO also has been used in clinical trials as a chemopreventive and chemotherapeutic agent, but its clinical utility has been limited by its side effect of ototoxicity.…”

Food Restriction Inhibits the Growth of Intestinal Polyps in Multiple Intestinal Neoplasia Mouse

“…The intestinal polyps were classified into two groups according to their diameter, ≤2 mm and >2 mm. 15) Microscopic studies were performed with sagittal sections of formalin-fixed and paraffin-embedded tissues obtained from the four intestinal areas. These sections were routinely processed for paraffin embedding and sectioned at 3 µm thickness.…”