The Applicant has observed that calcitriol could enhance 2-O-tetradecanoylphorbol-13-acetate (TPA) - induced tumorigenic transformation of the pre-neoplastic mouse epidermal JB6 line. Treatment of these cells with calcitriol by itself didnot induce cell transformation nor did it lead to phosphorylation of osteopontin (POPN). In contrast she observed that induction of POPN and its secretion correlated with tumorigenesis when the cells were stimulated with TPA or TPA and calcitriol. The Applicant proposes to pursue the mechanisms by which calcitriol enhances TPA induced tumorigenesis. She conjectures that calcitriol enhances TPA-induced tumorigenesis by regulating transcription of a combination of genes including the gene for POPN which confers upon these cells a transformed phenotype. The Applicant proposes four specific aims. These include: the employment of calcitriol analogs with defined functions (i.e., binding to the vitamin D receptor or mediating cellular calcium fluxes) to determine if synergism of calcitriol with TPA arises from genomic and/or nongenomic effects of calcitriol. 2) She plans to determine if calcitriol treatment of her cell line affects TPA induced expression of members of the fos and jun families of protooncogenes as well as enhances the expression of protein kinase C. 3) She plans to develop antisense constructs to the OPN gene to determine whether expression of OPN is necessary for TPA-induced tumorigenic transformation. 4) Finally, she plans to use differential display of MRNA to investigate possible unique gene expression in the cell line treated with TPA and/or calcitriol.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA069688-01
Application #
2113720
Study Section
Special Emphasis Panel (ZRG4-NTN (06))
Project Start
1995-09-01
Project End
2000-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Allied Health Profes
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Chang, Pi-Ling; Blair, Harry C; Zhao, Xiaochu et al. (2006) Comparison of fetal and adult marrow stromal cells in osteogenesis with and without glucocorticoids. Connect Tissue Res 47:67-76
Chang, Pi-Ling; Cao, Minhton; Hicks, Patricia (2003) Osteopontin induction is required for tumor promoter-induced transformation of preneoplastic mouse cells. Carcinogenesis 24:1749-58
Chang, Pi-Ling; Tucker, Mary A; Hicks, Patricia H et al. (2002) Novel protein kinase C isoforms and mitogen-activated kinase kinase mediate phorbol ester-induced osteopontin expression. Int J Biochem Cell Biol 34:1142-51
Chang, P L; Chambers, A F (2000) Transforming JB6 cells exhibit enhanced integrin-mediated adhesion to osteopontin. J Cell Biochem 78:23-Aug
Tucker, M A; Chang, P L; Prince, C W et al. (1998) TPA-mediated regulation of osteopontin in human malignant glioma cells. Anticancer Res 18:807-12
Chang, P L; Lee, T F; Garretson, K et al. (1997) Calcitriol enhancement of TPA-induced tumorigenic transformation is mediated through vitamin D receptor-dependent and -independent pathways. Clin Exp Metastasis 15:580-92