Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli 1638N/1 mice

Kan Yang, Sergio A. Lamprecht, Hiroharu Shinozaki, Kunhua Fan, WanCai Yang, Harold L. Newmark, Levy Kopelovich, Winfried Edelmann, Bo Jin, Claudia Gravaghi, Leonard H. Augenlicht, Raju Kucherlapati, Martin Lipkin

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Abstract

Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)1638N/+ mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc1638N/+ mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 ± 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc1638N/+ mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.

Original languageEnglish (US)
Pages (from-to)1658-1663
Number of pages6
JournalJournal of Nutrition
Volume138
Issue number9
StatePublished - Sep 2008

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Dietary Calcium
Adenomatous Polyposis Coli
cholecalciferol
Cholecalciferol
Cyclin D1
cyclins
carcinogenesis
Intestines
Carcinogenesis
intestines
apoptosis
Apoptosis
Diet
calcium
mice
diet
epithelium
Epithelium
neoplasms
mutation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Food Science

Cite this

Yang, K., Lamprecht, S. A., Shinozaki, H., Fan, K., Yang, W., Newmark, H. L., ... Lipkin, M. (2008). Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli 1638N/1 mice. Journal of Nutrition, 138(9), 1658-1663.

Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli 1638N/1 mice. / Yang, Kan; Lamprecht, Sergio A.; Shinozaki, Hiroharu; Fan, Kunhua; Yang, WanCai; Newmark, Harold L.; Kopelovich, Levy; Edelmann, Winfried; Jin, Bo; Gravaghi, Claudia; Augenlicht, Leonard H.; Kucherlapati, Raju; Lipkin, Martin.

In: Journal of Nutrition, Vol. 138, No. 9, 09.2008, p. 1658-1663.

Research output: Contribution to journalArticle

Yang, K, Lamprecht, SA, Shinozaki, H, Fan, K, Yang, W, Newmark, HL, Kopelovich, L, Edelmann, W, Jin, B, Gravaghi, C, Augenlicht, LH, Kucherlapati, R & Lipkin, M 2008, 'Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli 1638N/1 mice', Journal of Nutrition, vol. 138, no. 9, pp. 1658-1663.
Yang, Kan ; Lamprecht, Sergio A. ; Shinozaki, Hiroharu ; Fan, Kunhua ; Yang, WanCai ; Newmark, Harold L. ; Kopelovich, Levy ; Edelmann, Winfried ; Jin, Bo ; Gravaghi, Claudia ; Augenlicht, Leonard H. ; Kucherlapati, Raju ; Lipkin, Martin. / Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli 1638N/1 mice. In: Journal of Nutrition. 2008 ; Vol. 138, No. 9. pp. 1658-1663.
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abstract = "Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)1638N/+ mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc1638N/+ mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 ± 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc1638N/+ mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.",
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