Abstract

This proposal examines the ability of vitamin-D and its derivatives to regulate cell growth in colonic cancer. The applicant and his coworkers have shown that F6-D3, a fluorinated, non-calcemic analog of 1-alpha,25 (OH)2-D3 reduced the incidence of colonic adenomas and prevented the development of adenocarcinomas in experimental models. In order to understand the role of vitamin D3 in colonic normal and abnormal function, studies are proposed in normal rat colon and in CaCo-2 cells, a cell line derived from a human colonic adenocarcinoma. The cells exhibit similar signal transduction mechanisms and respond in similar fashion to vitamin D as their normal counterparts. Previous studies have shown that vitamin D and F6-D3 decreased cellular proliferation in these cells, while more recent studies have shown that they induce growth arrest in the G1 phase of cell cycle and bring about apoptosis. Accordingly the specific aims of the proposal are to characterize the mechanisms involved in inhibition of cellular proliferation in CaCo-2 cells and the actions of the secosteroids in inducing apoptosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK039573-09
Application #
2684180
Study Section
Special Emphasis Panel (ZRG2-NTN (01))
Program Officer
May, Michael K
Project Start
1989-07-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Khare, Sharad; Cerda, Sonia; Wali, Ramesh K et al. (2003) Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer. Cancer Res 63:3517-23
Wali, Ramesh K; Stoiber, Debra; Nguyen, Lan et al. (2002) Ursodeoxycholic acid inhibits the initiation and postinitiation phases of azoxymethane-induced colonic tumor development. Cancer Epidemiol Biomarkers Prev 11:1316-21
Wali, Ramesh K; Khare, Sharad; Tretiakova, Maria et al. (2002) Ursodeoxycholic acid and F(6)-D(3) inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: roles of cyclin D1 and E-cadherin. Cancer Epidemiol Biomarkers Prev 11:1653-62
Alrefai, W A; Scaglione-Sewell, B; Tyagi, S et al. (2001) Differential regulation of the expression of Na(+)/H(+) exchanger isoform NHE3 by PKC-alpha in Caco-2 cells. Am J Physiol Cell Physiol 281:C1551-8
Cerda, S R; Bissonnette, M; Scaglione-Sewell, B et al. (2001) PKC-delta inhibits anchorage-dependent and -independent growth, enhances differentiation, and increases apoptosis in CaCo-2 cells. Gastroenterology 120:1700-12
Scaglione-Sewell, B A; Bissonnette, M; Skarosi, S et al. (2000) A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: roles of cyclin E, p21Waf1, and p27Kip1. Endocrinology 141:3931-9
Chen, A; Davis, B H; Bissonnette, M et al. (1999) 1,25-Dihydroxyvitamin D(3) stimulates activator protein-1-dependent Caco-2 cell differentiation. J Biol Chem 274:35505-13
Abraham, C; Scaglione-Sewell, B; Skarosi, S F et al. (1998) Protein kinase C alpha modulates growth and differentiation in Caco-2 cells. Gastroenterology 114:503-9
Wali, R K; Bissonnette, M; Skarosi, S et al. (1998) 1,25-Dihydroxyvitamin D3 targets PKC-betaII but not PKC-alpha to the basolateral plasma membranes of rat colonocytes. Biochem Biophys Res Commun 250:48-52
Scaglione-Sewell, B; Abraham, C; Bissonnette, M et al. (1998) Decreased PKC-alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells. Cancer Res 58:1074-81

Showing the most recent 10 out of 32 publications