Abstract
Short chain fatty acids may protect colonic mucosa against neoplastic transformation by modulating colonocyte phenotype, DNA synthesis, and c-myc levels. To test this hypothesis, nonmalignant and malignant human colonocytes were isolated from surgical specimens and treated with 10 mM acetate, propionate, or butyrate. Markers of cellular phenotype, DNA synthesis, and c-myc protein levels were assayed by alkaline phosphatase and dipeptidyl dipeptidase IV activities, [3H]thymidine labeling, and western blotting, respectively. Butyrate, in particular, exerted discordant effects on alkaline phosphatase (P < 0.05), and c-myc levels (P < 0.05, N ≥ 6) in nonmalignant and malignant human colonocytes. DPDD was unaffected by any of the short chain fatty acids tested. [3H]Thymidine labeling was differentially stimulated by short chain fatty acids in both cell types and greater DNA synthesis rates were observed in malignant colonocytes (P < 0.005, N = 16). These data suggest that in vitro, butyrate, in particular, may differentially modulate phenotype, DNA synthesis, and c-myc in nonmalignant and malignant human colonocytes.
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REFERENCES
Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Stampfer MJ, Rosner B, Speizer FE, Willet WC: Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 340:169–176, 1999
Meyer F, White E: Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epidemiol 138:225–236, 1993
Sukuki K, Suzuki K, Mitsuoka T: Effect of low-fat, high-fat, and fiber-supplemented high-fat diets on colon cancer risk factors in feces of healthy subjects. Nutr Cancer 18:63–71, 1992
Madar Z, Thorne R: Dietary fiber. Prog Food Nutr Sci 11:153–174, 1987
Jacobs LR: Relationship between dietary fiber and cancer: Metabolic, physiologic, and cellular mechanisms. Proc Soc Exp Biol Med 183:299–310, 1986
Clausen MR, Bonnen H, Mortensen PB: Colonic fermentation of dietary fibre to short chain fatty acids in patients with adenomatous polyps and colonic cancer. Gut 32:923–928, 1991
Casterline JL, Oles CJ, Ku Y: In vitro fermentation of various food fiber fractions. J Agric Food Chem 45:2463–7, 1997
Basson MD, Turowski GA, Rashid Z, Hong F, Madri JA: Regulation of human colonic cell line proliferation and phenotype by sodium butyrate. Dig Dis Sci 41:1986–93, 1996
Gibson PR, Moeller I, Kagelari O, Folino M, Young GP: Contrasting effects of butyrate on the expression of phenotypic markers of differentiation in neoplastic and non-neoplastic colonic epithelial cells in vitro. J Gastroenterol Hepatol 7:165–72, 1992
Basson MD, Sgambati SA: Effects of short chain fatty acids on human rectosigmoid mucosal colonocyte brush-border enzymes. Metabolism 47:133–134, 1998
Basson MD, Emenaker NJ, Hong F. Differential modulation of human (Caco-2) colon cancer cell line phenotype by short chain fatty acids. Proc Soc Exp Biol Med 217:476–83, 1998
Whitehead RH, Young GP, Bhathal PS: Effects of short chain fatty acids on a new human colon carcinoma cell line (LIM1215). Gut 27:1457–63, 1986
Emenaker NJ, Basson MD. Short chain fatty acids inhibit human (SW1116) colon cancer cell invasion by reducing urokinase plasminogen activator activity and stimulating TIMP-1 and TIMP-2 activities, rather than via MMP modulation. J Surg Res 76:41–6, 1998
Young GP, Gibson PR. Butyrate and the colorectal cancer cell. In Short Chain Fatty Acids. Falk Symposium 73. HJ Binder, J Cummings, KH Soergel (eds). Boston, Kluwer Academic Press, 1993, pp 148–60
Gibson PR, Van de Pol E, Maxwell IE, Gabriel A, Doe WF: Isolation of colonic crypts that maintain structural and metabolic viability in vitro. Gastroenterology 96:283–91, 1989
Young GP, Gibson PR: Contrasting effects on butyrate on proliferation and differentiation of normal and neoplastic cells. In Roche AF (ed) Short Chain Fatty Acids: Metabolism and Clinical Importance. Report of the Tenth Ross Conference on Medical Research. Columbus, Ohio, Ross Laboratories, 1991, pp 50–5
Takahashi T, Satou M, Watanabe N, Sakaitani Y, Takagi A, Uchida K, Ikeda M, Moriyama R, Matsumoto K, Morotomi M: Inhibitory effect of microfibril wheat bran on azoxymethaneinduced colon carcinogenesis in CF1 mice. Cancer Lett 141:139–136, 1999
Fitch MD, Fleming SE: Metabolism of short-chain fatty acids by rat colonic mucosa in vivo. Am J Physiol 277(1 Pt 1):G31–40, 1999
Young GP, Macrae FA, Gibson PR, Alexeyeff M, Whitehead R: Brush border hydrolases in normal and neoplastic epithelium. J Gastroenterol Heptalol 7:347–57, 1992
Peake MJ, Pejakovic M, White GH: Quantitative method for determining serum alkaline phosphatase isoenzyme activity: Estimation of intestinal component. J Clin Pathol 41:202–6, 1988
Sundaram U, Knickelbein RG, Dibbins JW: pH regulation in ileum: Na-H and Cl-HCO3 exchange in isolated crypt and villus cells. Am J Physiol 260:G440–G9, 1991
Turowski GA., Rashid Z., Hong F, Madri JA, Basson MD: Glutamine modulates phenotype and stimulates proliferation in human colon cancer cell lines. Cancer Res 54:5974–80, 1994
Basson MD, Modlin IM, Flynn SD, Jena BP, Madri JA: Independent modulation of enterocyte migration and proliferation by growth factors, matrix proteins and pharmacologic agents in an in vitro model of mucosal healing. Surgery 112:299–308, 1992
Gustin MC, Goodman DB: Isolation of brush-border membrane from the rabbit descending colon epithelium. J Biol Chem 256:10651–6, 1981
Gorvel JP, Ferrero A, Chambraud L, Rigal A, Bonicel J, Maroux S: Expression of sucrase-isomaltase and dipeptidylpeptidase IV in human small intestine and colon. Gastroenterology 101:618–25, 1991
Fleming SE, O'Donnell AU, Perman JA: Influence of frequent and long-term bean consumption on colonic function and fermentation. Am J Clin Nutr 41:909–918, 1985
Fleming SE, Marthinsen D, Kuhnlein H: Colonic function and fermentation in men consuming high fiber diets. J Nutr 113:2535–44, 1983
Barnard JA, Warwick G: Butyrate rapidly induces growth inhibition and differentiation in HT-29 cells. Cell Growth Differ 4:495–501, 1993
Souleiimani A, Asselin C: Regulation of c-myc expression by sodium butyrate in the colon carcinoma cell line Caco-2. FEBS Lett 326:45–50, 1993
Lev R, Griffiths WC: Colonic and small intestinal alkaline phosphatase. A histochemical and biochemical study. Gastroenterology 82(6):1427–1435, 1982
Velcich A, Palumbo L, Jarry A, Laboisse C, Racevskis J, Augenlicht L: Patterns of expression of lineage-specific markers during the in vitro-induced differentiation of HT29 colon carcinoma cells. Cell Growth Differ 6:749–57, 1995
Basson MD, Turowski G, Emenaker NJ: Regulation of human (Caco-2) intestinal epithelial cell differentiation by extracellular matrix proteins Exp Cell Res 225:301–5, 1996
Basson MD, Modlin IM, Madri JA: Human enterocyte (Caco-2) migration is modulated in vitro by extracellular matrix composition and epidermal growth factor. J Clin Invest 90:15–23, 1992
Sgambati SA, Turowski GA, Basson MD: Peptide YY selectively stimulates expression of the colonocytic phenotype. J Gastrointest Surg 1:561–8, 1997
Schroder C, Eckert K, Maurer HR: Tributyrin induces growth inhibitory and differentiating effects on HT-29 colon cancer cells in vitro. Int J Oncol 13:1335–1340, 1998
Heruth DP, Zirnstein GW, Bradley JF, Rothberg PG: Sodium butyrate causes an increase in the block to transcriptional elongation in the c-myc gene in SW837 rectal carcinoma cells. J Biol Chem 268:20466–72, 1993
Chung YS, Song IS, Erickson RH, Sleisenger MH, Kim YS: Effects of growth and sodium butyrate on brush border membrane-associated hydrolases in human colorectal cancer cell lines. Cancer Res 45:2946–82, 1985
Barshishat M, Polak-Charcon S, Schwartz B: Butyrate regulates E-cadherin transcription, isoform expression and intracellular position in colon cancer cells. Br J Cancer 82(1):195–203, 2000
Rickard KL, Gibson PR, Wilson NJ, Mariadason JM, Phillips WA: Short-chain fatty acids reduce expression of specific protein kinase C isoforms in human colonic epithelial cells. J Cell Physiol 182(2):222–31, 2000
Bordonaro M, Mariadason JM, Aslam F, Heerdt BG, Augenlicht LH: Butyrate-induced apoptotic cascade in colonic carcinoma cells: Modulation of the beta-catenin-Tcf pathway and concordance with effects of sulindac and trichostatin A but not curcumin. Cell Growth Differ 10(10):713–20, 1999
Chung YS, Song IS, Erickson RH, Sleisenger MH, Kim YS: Effects of growth and sodium butyrate on brush border membrane-associated hydrolases in human colorectal cancer cell lines. Cancer Res 45:2976–82, 1985
Archer S, Meng S, Wu J, Johnson J, Tang R, Hodin R: Butyrate inhibits colon carcinoma cell growth through two distinct pathways. Surgery 124:248–53, 1998
Archer SY, Meng S, Shei A, Hodin RA: p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc Natl Acad Sci USA 95(12):6791–6796, 1998
Diener M, Helmle-Kolb C, Murer H, Scharrer E: Effect of short chain fatty acids on cell volume and intracellular pH in rat distal colon. Pflugers Arch Eur J Physiol 424:216–23, 1993
Zoran DL, Barhoumi R, Burghardt RC, Chapkin RS, Lupton JR: Diet and carcinogen alter luminal butyrate concentration and intracellular pH in isolated rat colonocytes. Nutr Cancer 27:222–30, 1997
Chu S, Montrose MH: Extracellular pH regulation in microdomains of colonic crypts: Effects of short chain fatty acids. Proc Natl Acad Sci USA 92:3303–7, 1995
Rottleb C, Bornkamm GW, Polack A: Among 17 inducers of differentiation only sodium butyrate causes a permanent downregulation of c-myc in Burkitt's lymphoma. Int J Cancer 62:697–702, 1995
Deng G, Liu G, Hu L, Gum JR Jr, Kim YS: Transcriptional regulation of the human placental-like alkaline phosphatase gene and mechanisms involved in its induction by sodium butyrate. Cancer Res 52:3378–83, 1992
Alberts DS, Martinez ME, Roe DJ, Guillen-Rodriguez JM, Marshall JR, van Leeuwen JB, Reid ME, Ritenbaugh C, Vargas PA, Bhattacharyya AB, Earnest DL, Sampliner RE: Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network. N Engl J Med 342(16):1156–62, 2000
Schatzkin A, Lanza E, Corle D, Lance P, Iber F, Caan B, Shike M, Weissfeld J, Burt R, Cooper MR, Kikendall JW, Cahill J: Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med 342:1149–55, 2000
Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Stampfer MJ, Rosner B, Speizer FE, Willett WC: Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 21:340:169–76, 1999
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Emenaker, N.J., Basson, M.D. Short Chain Fatty Acids Differentially Modulate Cellular Phenotype and c-myc Protein Levels in Primary Human Nonmalignant and Malignant Colonocytes. Dig Dis Sci 46, 96–105 (2001). https://doi.org/10.1023/A:1005661809250
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DOI: https://doi.org/10.1023/A:1005661809250