Nature Reviews Cancer 3, 552 (2003); doi:10.1038/nrc1149


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RISK AND PREVENTION
An aspirin a day...

Ezzie Hutchinson

...keeps colorectal cancer away. Regular use of aspirin has been
shown to prevent or inhibit the development of colorectal cancer.
However, Maria Elena Martinez and colleagues now show that the degree
of risk reduction that results from taking aspirin depends on the
variation of the ornithine decarboxylase (ODC) gene between
individuals. Both aspirin and ODC independently affect the same
metabolic pathway.

ODC is a key enzyme in the synthesis of polyamines — compounds that
are essential for cell proliferation. Increased levels of polyamines
are implicated in hereditary colorectal cancers that have mutations
in the adenomatous polyposis coli (APC) gene. APC influences the
expression of c-MYC (and its antagonist MAD1), which
transcriptionally regulates ODC — mutant APC leads to an increase in
ODC. Expression of ODC is also increased in patients with colorectal
cancer who have no genetic risk.

Activity of the ODC promoter depends on cooperative interactions
between two binding sites for c-MYC, and a polymorphic site (A316G)
has been identified in the region between these binding sites that
affects ODC-promoter activity. The authors genotyped 688 participants
in an adenoma recurrence trial for ODC and found that 56% were
homozygous for the G allele, 6% were homozygous for the A allele and
the remaining 38% were heterozygous at this locus. Participants
homozygous for A had a 0.48 odds of recurrence compared with
homozygous G individuals. In addition, 30% of the study participants
took aspirin regularly, and these people were 0.32 times less likely
to have adenoma recurrence. If these aspirin users were also
homozygous for the ODC A allele, their odds of recurrence were
significantly reduced to 0.10.

So, does the A316G polymorphism affect the activity of ODC? When wild-
type APC was expressed in HT29 colon-tumour cells — mimicking normal
colon epithelia — c-MYC was suppressed and MAD1 was induced. If the
HT29-APC cells were transfected with ODC/A, activity of the ODC
promoter was significantly reduced, as assessed in a luciferase
assay. Transfection of ODC/G had no such effect. If MAD1 was
constitutively expressed in the HT29-APC cells, a 78% A-allele
specific inhibition of ODC-promoter activity was observed, indicating
that MAD1 directly affects the ODC promoter.

Next, the authors investigated the role of aspirin in the ODC
metabolic pathway. Treatment of the ODC/G- and ODC/A-transfected HT29-
APC cell lines with therapeutic concentrations of aspirin had no
effect on ODC promoter activity, or on ODC enzyme activity. However,
aspirin was shown to induce the activity of an enzyme,
spermidine/spermine N-1-acetyltransferase (SSAT), which is involved
in polyamine catabolism and export. Expression of SSAT has recently
been shown to be induced by another non-steroidal anti-inflammatory
drug (NSAID), indomethacin.

So, ODC polymorphism and aspirin work via unique mechanisms to
influence a common metabolic pathway — that of polyamine synthesis.
Studies are underway to assess the benefit of combining NSAIDs with
ODC inhibitors in individuals with a high risk of developing
colorectal cancer.


References and links

ORIGINAL RESEARCH PAPER
Martinez, M. E. et al. Pronounced reduction in adenoma recurrence
associated with aspirin use and a polymorphism in the ornithine
decarboxylase gene. Proc. Natl Acad. Sci. USA 100, 7859-7864 (2003) |
Article | PubMed | ChemPort