Work from this and other laboratories has demonstrated that 1,25-dihydroxyvitamin D3 is a potent inhibitor of tumor cell growth and metastasis and an inducer of cell differentiation. The goal is to elucidate the mechanism through which this hormone regulates these important processes and to assess the usefulness of 1,25-(OH)2D3 in treating neoplastic disease. Our studies on human osteosarcoma cells indicate that the effects of 1,25-(OH)2D3 are potentiated by reduced extracellular calcium concentrations. Furthermore, this hormone may change the subcellular localization of protein kinase C and alter intracellular calcium concentrations. Growth inhibition is accompanied by changes in cell morphology and adhesion and increased synthesis of the cell surface glycoprotein, fibronectin, an important molecule for cell: substrate attachment and normal morphology. Fibronectin may also be an important determinant of a tumor's metastatic potential in vivo. This project will test the following hypotheses: 1) That 1,25-(OH)2D3 inhibits cell growth by altering intracellular calcium concentrations which in turn modifies protein kinase C: membrane interactions. Studies will examine the calcium dependence of the 1,25-(OH)2D3 response, measure intracellular calcium concentrations and monitor changes in protein kinase C between membrane and soluble pools. 2) That 1,25-(OH)2D3 controls cell morphology and metastasis by stimulating fibronectin gene expression. Experiments will examine effects of 1,25-(OH)2D3 on fibronectin synthesis and degradation and measure fibronectin gene expression using a specific cDNA probe. The in vivo relevance of these studies will be assessed by examining the role of vitamin D status in regulating FN levels in transplatable tumors. The possible role of FN in bone development will also be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK035317-03
Application #
3233607
Study Section
General Medicine B Study Section (GMB)
Project Start
1986-09-17
Project End
1989-02-28
Budget Start
1988-09-01
Budget End
1989-02-28
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Public Health
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Xiao, G; Cui, Y; Ducy, P et al. (1997) Ascorbic acid-dependent activation of the osteocalcin promoter in MC3T3-E1 preosteoblasts: requirement for collagen matrix synthesis and the presence of an intact OSE2 sequence. Mol Endocrinol 11:1103-13
McCauley, L K; Koh, A J; Beecher, C A et al. (1996) PTH/PTHrP receptor is temporally regulated during osteoblast differentiation and is associated with collagen synthesis. J Cell Biochem 61:638-47
Marsh, M E; Munne, A M; Vogel, J J et al. (1995) Mineralization of bone-like extracellular matrix in the absence of functional osteoblasts. J Bone Miner Res 10:1635-43
Winnard, R G; Gerstenfeld, L C; Toma, C D et al. (1995) Fibronectin gene expression, synthesis and accumulation during in vitro differentiation of chicken osteoblasts. J Bone Miner Res 10:1969-77
Franceschi, R T; Wilson, J X; Dixon, S J (1995) Requirement for Na(+)-dependent ascorbic acid transport in osteoblast function. Am J Physiol 268:C1430-9
McCauley, L K; Koh, A J; Beecher, C A et al. (1995) Effects of differentiation and transforming growth factor beta 1 on PTH/PTHrP receptor mRNA levels in MC3T3-E1 cells. J Bone Miner Res 10:1243-55
Franceschi, R T; Iyer, B S; Cui, Y (1994) Effects of ascorbic acid on collagen matrix formation and osteoblast differentiation in murine MC3T3-E1 cells. J Bone Miner Res 9:843-54
Franceschi, R T; Iyer, B S (1992) Relationship between collagen synthesis and expression of the osteoblast phenotype in MC3T3-E1 cells. J Bone Miner Res 7:235-46
Giuliano, A R; Franceschi, R T; Wood, R J (1991) Characterization of the vitamin D receptor from the Caco-2 human colon carcinoma cell line: effect of cellular differentiation. Arch Biochem Biophys 285:261-9
Franceschi, R T; Young, J (1990) Regulation of alkaline phosphatase by 1,25-dihydroxyvitamin D3 and ascorbic acid in bone-derived cells. J Bone Miner Res 5:1157-67

Showing the most recent 10 out of 12 publications