Pronounced Reduction in Adenoma Recurrence Associated with Aspirin Use and a Polymorphism in the Ornithine Decarboxylase Gene

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-06, Vol.100 (13), p.7859-7864
• Main Authors: Martínez, María Elena, O'Brien, Thomas G., Fultz, Kimberly E., Babbar, Naveen, Yerushalmi, Hagit, Qu, Ning, Guo, Yongjun, Boorman, David, Einspahr, Janine, Alberts, David S., Gerner, Eugene W.
• Format: Article
• Language: English
• Subjects: Adenoma; Adenoma - drug therapy; Adenoma - pathology; Adenoma - prevention & control; Adult; Aged; Aged, 80 and over; Alleles; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Aspirin; Aspirin - therapeutic use; Base Sequence; Biological Sciences; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Dose-Response Relationship, Drug; Enzyme activity; Female; Genes; Genetic Predisposition to Disease; Genetics; Genotype; Genotypes; HT29 cells; Humans; Male; Middle Aged; Models, Biological; Molecular Sequence Data; Neoplasia; Ornithine Decarboxylase - genetics; Plasmids - metabolism; Polyamines; Polyamines - metabolism; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Structure, Tertiary; Recurrence; RNA; RNA - metabolism; Time Factors; Transfection; Tumor Cells, Cultured; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1332465100

Most sporadic colon adenomas acquire mutations in the adenomatous polyposis coli gene (APC) and show defects in APC-dependent signaling. APC influences the expression of several genes, including the c-myc oncogene and its antagonist Mad1. Ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is a transcriptional target of c-myc and a modifier of APC-dependent tumorigenesis. A single-nucleotide polymorphism exists in intron 1 of the human ODC gene, which lies between two myc-binding domains. This region is known to affect ODC transcription, but no data exist on the relationship of this polymorphism to risk of colorectal neoplasia in humans. We show that individuals homozygous for the minor ODC A-allele who reported using aspirin are ≈0.10 times as likely to have an adenoma recurrence as non-aspirin users homozygous for the major G-allele. Mad1 selectively suppressed the activity of the ODC promoter containing the A-allele, but not the G-allele, in a human colon cancer-derived cell line (HT29). Aspirin (≥10 µM) did not affect ODC allele-specific promoter activity but did activate polyamine catabolism and lower polyamine content in HT29 cells. We propose that the ODC polymorphism and aspirin act independently to reduce the risk of adenoma recurrence by suppressing synthesis and activating catabolism, respectively, of colonic mucosal polyamines. These findings confirm the hypothesis that the ODC polymorphism is a genetic marker for colon cancer risk, and support the use of ODC inhibitors and aspirin, or other nonsteroidal antiinflammatory drugs (NSAIDs), in combination as a strategy for colon cancer prevention.