Abstract
Polyamines are increased in many intraepithelial neoplasia, which are risk factors for cancer in humans (1). Ornithine decarboxylase (ODC1), the first enzyme in polyamine synthesis, is regulated in part by Ebox transcription factors including MYC and MAD family members. The ODC1 gene contains several single nucleotide polymorphisms (SNPs) which are associated with risk of colorectal neoplasia. A SNP located 316 nucleotides from the start of transcription (rs2302615) has functional consequences for Ebox transcription factor binding and promoter activity. Both the transcription activator MYC and transcriptional repressors in the MAD family preferentially bind the ODC promoter element containing the minor A allele, which is flanked by two canonical E-boxes, resulting in allele-specific expression (2, 3). This SNP is associated with both risk of metachronous colorectal adenoma (CRA), in several independent studies (2, 4), and survival of patients with stages I-III colon cancer (3). The ODC1 SNP was also found to be predictive of reduced risk of CRA in association with aspirin use by three independent groups (2, 4, 5). The mechanism underlying the relationship between the ODC1 SNP and aspirin appears to involve the action of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on polyamine catabolism and export. NSAIDs, including aspirin and sulindac, and celecoxib transcriptionally activate SAT1, a spermidine/spermine acetyltransferase, by unique mechanisms (6-8). Acetylation targets these polyamines for export by an SLC3A2-dependent arginine antiporter (9). Thus, NSAIDs and celecoxib, by activating polyamine export, complement ODC1 inhibitors, which suppress polyamine synthesis, to reduce tissue polyamine contents. In a prospective, randomized, placebo-controlled clinical trial of difluoromethylornithine (DFMO), a selective ODC1 inhibitor, and the NSAID sulindac for three years, combination treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple CRAs, in patients with prior colon polyps (10). The 30% rate of non-advanced CRA development in the treatment arm was strongly associated with both the ODC1 SNP and dietary polyamines (11). Consideration of homeostatic regulatory processes, supported by measurements of tissue polyamine contents in participants in this trial, support the interpretation that decreased ODC transcription, resulting from the ODC1 SNP, is associated with altered polyamine transport. Treatment-associated toxicities were rare and associated with pretreatment clinical and genetic risk factors. The ODC1 SNP was predictive of ototoxicity in this trial (11). These studies identify genetic variability in ODC1, a MYC target gene, as a prognostic factor for colorectal carcinogenesis and as a predictive factor for treatments targeting this pathway. The role(s) of other ODC1 SNPs in colorectal or other cancers remains to be established.
References:
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Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL01-04.
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