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.
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