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Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1,
E M Schmelz1, M C Sullards, D L Dillehay
1Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
Abstract:
Dietary sphingomyelin (SM) inhibits early stages of colon cancer (appearance of aberrant crypt foci, ACF) and decreases the proportion of adenocarcinomas vs. adenomas in 1,2-dimethylhydrazine (DMH)-treated CF1 mice. To elucidate the structural specificity of this inhibition, the effects of the other major sphingolipids in milk (glycosphingolipids) were determined. Glucosylceramide (GluCer), lactosylceramide (LacCer) and ganglioside G(D3) were fed individually to DMH-treated (six doses of 30 mg/kg body weight) female CF1 mice at 0.025 or 0.1 g/100 g of the diet for 4 wk. All reduced the number of ACF by > 40% (P < 0.001), which is comparable to the reduction by SM in earlier studies. Immunohistochemical analysis of the colons revealed that sphingolipid feeding also reduced proliferation, with the most profound effect (up to 80%; P < 0.001) in the upper half of the crypts. Since the bioactive backbones of the glycosphingolipids (i.e., ceramide and other metabolites) are the likely mediators of these effects, the susceptibility of these complex sphingolipids to digestion in the colon was examined by incubating 500 microgram of each sphingolipid with colonic segments from mice and analysis of substrate disappearance and product formation by tandem mass spectrometry. All of the sphingolipids (including SM) disappeared over time with a substantial portion appearing as ceramide. Partially hydrolyzed intermediates (such as GluCer from LacCer or G(D3)) were not detected, which suggests that the cleavage involves colonic (or microflora) endoglycosidases. In summary, consumption of dairy SM and glycosphingolipids suppresses colonic cell proliferation and ACF formation in DMH-treated mice; hence, many categories of sphingolipids affect these key events in colon carcinogenesis.
Insights
Dietary sphingolipids, including sphingomyelin (SM) and glycosphingolipids, significantly inhibit colon cancer development by reducing aberrant crypt foci (ACF) and cell proliferation in mice.
Area of Science:
- Nutrition and Cancer
- Gastroenterology
- Molecular Biology
Background:
- Dietary sphingomyelin (SM) is known to inhibit early colon cancer stages.
- The role of other milk sphingolipids, like glycosphingolipids, in colon carcinogenesis is less understood.
Purpose of the Study:
- To investigate the structural specificity of sphingolipid inhibition on colon cancer.
- To determine the effects of dietary glycosphingolipids (Glucosylceramide, Lactosylceramide, Ganglioside G(D3)) on colon cancer development.
Main Methods:
- 1,2-dimethylhydrazine (DMH)-treated CF1 mice were fed diets containing SM or specific glycosphingolipids.
- Aberrant crypt foci (ACF) formation and colonic cell proliferation were assessed.
- Sphingolipid digestion and metabolite formation in colonic segments were analyzed using tandem mass spectrometry.
Main Results:
- All tested sphingolipids (SM, Glucosylceramide, Lactosylceramide, Ganglioside G(D3)) significantly reduced ACF formation (>40%).
- Sphingolipid feeding markedly decreased colonic cell proliferation, particularly in the upper crypts (up to 80%).
- Sphingolipids were digested in the colon primarily to ceramide, suggesting enzymatic breakdown by endoglycosidases.
Conclusions:
- Dietary sphingomyelin and various glycosphingolipids effectively suppress colon cancer initiation and progression in a mouse model.
- These findings highlight the broad impact of different sphingolipid categories on colon carcinogenesis.
- Ceramide, generated from sphingolipid digestion, is a likely mediator of these protective effects.
