Correlation between induction of the mac25 gene and anti-proliferative effects of 1 alpha,25(OH)(2)-D-3 on breast cancer and leukemic cells

In the differentiation of a myelomonocytic cell line U937 treated with 1 al pha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)-D-3], transient proliferat ion was observed prior to cell growth arrest. The expression of the p21 and p27 genes increased transiently and decreased quickly in the proliferation , suggesting that other genes may contribute to the growth arrest of the ce ll line after reduction of the p21 and p27 genes. The mac25 gene was isolat ed as a gene associated with cellular senescence and growth suppression. De spite a previous report that retinoic acid (RA) induced the mac25 gene, the mac25 gene did not increase in U937 cells treated with RA but did increase in the cells treated with 1 alpha ,25(OH)(2)-D-3. The high level of the ex pression of the mac25 gene was detected for four days after the 1 alpha ,25 (OH)(2)-D-3 treatment. Therefore, mac25 may contribute to the growth arrest of U937 cells treated with 1,25-D-3. The growth responses to 1 alpha ,25(O H)(2)-D-3 and the expression of the mac25 gene of three other cancel cell l ines (Saos-2, U20S and MCF7) were studied. Although the growth suppression was observed in MCF7 cells treated with 1 alpha ,25(OH)(2)-D-3 dose-depende ntly (1-100 nM of 1 alpha ,25(OH)(2)-D-3), the treatment of 1-100 nM of 1 a lpha ,25(OH)(2)-D-3 had no effect on the growth of Saos-2 and U20S cells. T he expression of the mac25 gene was up-regulated in MCF7 cells treated with 100 nM of 1 alpha ,25(OH)(2)-D-3, whereas no transcript of the mac25 gene was detected in Saos-2 and U20S cells even when they were treated with 100 nM of 1 alpha ,25(OH)(2)-D-3. These results suggest that the cellular respo nse to 1 alpha ,25(OH)(2)-D-3 may depend on the induction of the mac25 gene .