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SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol
1Center for Cancer Therapeutics, Ottawa Health Research Institute, and Department of Medicine, University of Ottawa, Ontario, Canada.
Abstract:
The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study the function of SirT1 in susceptibility to tumorigenesis. The number of intestinal polyps induced in mice carrying the Apc(min) mutation was unaffected by the SirT1 genotype although the average polyp size was slightly smaller in the SirT1-null animals. Similarly, the presence or absence of SirT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. We found that resveratrol topically applied to the skin profoundly reduced tumorigenesis. This chemoprotective effect was significantly reduced but not ablated in SirT1-null mice, suggesting that part of the protection afforded by resveratrol requires the SirT1-encoded protein. Thus, our results suggest that SirT1 does not behave like a classical tumor-suppressor gene but the antitumor activity of resveratrol is mediated at least in part by SirT1.
Insights
SirT1, a mammalian gene linked to aging, does not appear to suppress tumors. However, the anti-cancer benefits of resveratrol partly depend on SirT1 activity.
Area of Science:
- Genetics
- Molecular Biology
- Aging Research
Background:
- Class III histone deacetylase Sir2 extends lifespan in model organisms.
- SirT1 is the mammalian orthologue of Sir2 and a candidate for aging and age-related disease intervention.
Purpose of the Study:
- To investigate the role of SirT1 in tumorigenesis using SirT1-null mice.
- To determine if SirT1 acts as a tumor suppressor.
- To assess the involvement of SirT1 in the chemoprotective effects of resveratrol.
Main Methods:
- Utilized SirT1-null mice and mice with the Apc(min) mutation for intestinal polyp studies.
- Employed a two-stage carcinogenesis protocol to induce skin papillomas.
- Administered resveratrol topically to assess its chemoprotective effects in both wild-type and SirT1-null mice.
Main Results:
- SirT1 genotype did not affect intestinal polyp number but slightly reduced average polyp size in SirT1-null mice.
- SirT1 absence had no impact on the incidence or tumor load of chemically induced skin papillomas.
- Resveratrol significantly reduced tumorigenesis, with a partially diminished effect in SirT1-null mice.
Conclusions:
- SirT1 does not function as a classical tumor suppressor gene.
- The antitumor activity of resveratrol is, at least in part, mediated by SirT1.
- These findings highlight SirT1's role in mediating resveratrol's chemoprotective effects.
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