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

1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is a potent inhibitor of ke ratinocyte proliferation, as well as a stimulator of epidermal termina l differentiation. In the present studies, we investigated the influen ce of epidermal growth factor (EGF) and insulin on the antiproliferati ve and differentiation activities of 1,25(OH)(2)D-3. Our results indic ate the following: (1) EGF caused a dramatic potentiation of the 1,25( OH)(2) D-3-induced inhibition of H-3-thymidine incorporation into kera tinocytes in a dose-dependent manner; (2) insulin acted antagonistical ly on the EGF-dependent potentiation of the 1,25(OH)(2)D-3-induced ant iproliferative activity; (3) transforming growth factor-alpha potentia ted 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 wit h 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-depende nt cornified envelope formation. In conclusion, the antiproliferative activity of 1,25(OH)(2)D-3 in cultured normal human keratinocytes is g reatly enhanced by EGF or transforming growth factor-alpha and reduced by insulin. Insulin also inhibits 1,25(OH)(2)D-3-induced terminal dif ferentiation of cultured normal human keratinocytes.