THE ANTIPROLIFERATIVE AND DIFFERENTIATIVE ACTIVITIES OF 1,25-DIHYDROXYVITAMIN D-3 ARE POTENTIATED BY EPIDERMAL GROWTH-FACTOR AND ATTENUATED BY INSULIN IN CULTURED HUMAN KERATINOCYTES

1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is a potent inhibitor of keratinocyte proliferation, as well as a stimulator of epidermal terminal differentiation. In the present studies, we investigated the influence of epidermal growth factor (EGF) and insulin on the antiproliferative and differentiation activities of 1,25(OH)(2)D-3. Our results indicate the following: (1) EGF caused a dramatic potentiation of the 1,25(OH)(2) D-3-induced inhibition of H-3-thymidine incorporation into keratinocytes in a dose-dependent manner; (2) insulin acted antagonistically on the EGF-dependent potentiation of the 1,25(OH)(2)D-3-induced antiproliferative activity; (3) transforming growth factor-alpha potentiated 1,25(OH)(2)D-3-induced antiproliferative activity similar to EGF; (4) the EGF effect was not dependent upon 1,25(OH)(2)D-3 receptor mRNA upregulation; and (5) removal of insulin from medium supplemented with growth factors significantly potentiated the 1,25(OH)(2)D-3-induced inhibition on the number of basal cells and the 1,25(OH)(2)D-3-dependent cornified envelope formation. In conclusion, the antiproliferative activity of 1,25(OH)(2)D-3 in cultured normal human keratinocytes is greatly enhanced by EGF or transforming growth factor-alpha and reduced by insulin. Insulin also inhibits 1,25(OH)(2)D-3-induced terminal differentiation of cultured normal human keratinocytes.