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

The colorectal mucosa of pre-symptomatic individuals with familial adenomat ous polyposis (FAP) contains elevated levels of the proliferation-associate d polyamines. The Min mouse, like humans with FAP, expresses an abnormal ge notype for the APC tumor suppressor gene. In order to determine how APC mut ation influences intestinal tissue polyamine content, we measured steady-st ate RNA levels of ornithine decarboxylase (ODC), the first enzyme in polyam ine 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 sm all intestine and colon for ODC, decreased significantly in the small intes tine but not the colon for AZ and was not statistically different in either intestinal tissue for SSAT in Min mice compared with normal littermates, C onsistent 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 d ifluoromethylornithine (DFMO) suppressed small intestinal, but not colonic, polyamine content and tumor number. These data indicate that small intesti nal tissue polyamine content is elevated in Min mice by a mechanism involvi ng APC-dependent changes in ODC and AZ RNA. Further, ODC enzyme activity, w hich 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.