The E1A Oncogene Induces Resistance to the Effects of 1,25-Dihydroxyvitamin D3 on Inhibition of Growth of Mouse Keratinocytes

1,25-Dihydroxyvitamin D3 [l,25-(OH)2D3] inhibited DNA synthesis in transformed mouse keratinocytes (Pam212) in a time- and dose-dependent manner as measured by [3H]thymidine incorporation. To investigate the mechanism through which l,25-(OH)2D3 acts, we examined its effects on Pam212 cells further transformed with the E1 A oncogene. Here, we show that transformation of the cells with the E1A oncogene induced resistance to the effects of l,25-(OH)2D3 on inhibition of growth of Pam212 cells. While l,25-(OH)2D3 treatment increased the level of expression of vitamin D receptor mRNA 20-fold in parental cells, the E1A -transformed cells failed to express vitamin D receptor mRNA even after treatment with 1,25-(OH)2D3. Transfection of the E1A -transformed cell line with an expression construct encoding the vitamin D receptor restored receptor expression as well as the inhibition of growth by l,25-(OH)2D3. These results suggest that one of the mechanisms for acquisition of l,25-(OH)2D3 resistance induced by E1A may involve loss of vitamin D receptor inducibility by l,25-(OH)2D3.