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Supplement: AICR's 11th Annual Research Conference on Diet, Nutrition and Cancer

Short-Chain Fatty Acids Inhibit Invasive Human Colon Cancer by Modulating uPA, TIMP-1, TIMP-2, Mutant p53, Bcl-2, Bax, p21 and PCNA Protein Expression in an In Vitro Cell Culture Model^{1 ,2}

Nancy J. Emenaker³, Gloria M. Calaf^*, Dianne Cox, Marc D. Basson^** and Nassar Qureshi

Department of Physiology and Cellular Biophysics, The Center for Radiation Research, and Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY; Surgical Service, John D. Dingell VA Medical Center and Wayne State University, Detroit, MI; and the Department of Surgical Pathology, New York Presbyterian Medical Center, New York, NY ^{** *}

³To whom correspondence should be addressed. E-mail: nje7{at}columbia.edu.

High intakes of dietary fiber or resistant starches have been associated with a lower incidence of colon cancers. Because short-chain fatty acids (SCFA) such as butyrate are produced in the colonic lumen by the bacterial fermentation of dietary fibers and resistant starches, we hypothesized that SCFA may inhibit the development of invasive human colon cancers. To test this hypothesis, primary human invasive colonocytes were isolated from fresh surgical specimens and treated with 0.01 mol/L acetate, propionate or butyrate; cell invasion, cell adhesion, F-actin polymerization, urokinase plasminogen activator (uPA), tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-2 and mutant p53, Bcl-2, Bax, p21 and proliferating cell nuclear antigen (PCNA) protein expression levels were examined. Although each of the SCFA tested significantly reduced primary cell invasion, butyrate was the most potent, inhibiting primary invasive human colon cancer invasion by 54% (P < 0.0001). The effects of SCFA on primary cell invasion appeared to be independent of cell adhesion and F-actin polymerization but dependent on the inhibition of uPA (P < 0.05) and the stimulation of TIMP-1 and TIMP-2 activities (P < 0.05). Protein expression levels of mutant p53, p21, Bax, Bcl-2 and PCNA were significantly altered by each of the SCFA tested (P < 0.05). These data indicate that SCFA inhibit invasive human colon cancer by modulating proteolytic uPA and antiproteolytic TIMP-1 and TIMP-2 activities, but their mechanisms of action on tumor suppression, apoptosis and growth arrest may differ.

KEY WORDS: • butyrate • invasive colon cancer • urokinase plasminogen activator • dietary fiber • gene-nutrient interactions

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