Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene.
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 approximately 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 (>or=10 microM) 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.
Martinez
Maria Elena
ME
Arizona Cancer Center, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA. emartinez@azcc.arizona.edu
O'Brien
Thomas G
TG
Fultz
Kimberly E
KE
Babbar
Naveen
N
Yerushalmi
Hagit
H
Qu
Ning
N
Guo
Yongjun
Y
Boorman
David
D
Einspahr
Janine
J
Alberts
David S
DS
Gerner
Eugene W
EW
D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology* / Q000517:prevention & control; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012008:Recurrence; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011073:Polyamines; D012313:RNA; D009955:Ornithine Decarboxylase; D001241:Aspirin