DIFFERENTIAL REGULATION OF CHORIOCARCINOMA GENE-EXPRESSION BY DNA-SYNTHESIS INHIBITORS

We have previously shown that methotrexate (MTX) and hydroxyurea (HU) stimulate expression of the human chorionic gonadotropin alpha and pla cental alkaline phosphatase genes and repress the expression of the c- myc oncogene in BeWo choriocarcinoma cells. In order to determine whet her c-myc downregulation played a role in the induction of these place ntal genes, we treated BeWo choriocarcinoma cells with aphidicolin (AP H), and 6-diazo-5-oxo-L-norleucine (DON), and compared the effects of these drugs with that of MTX. All of these drugs downregulate c-myc ge ne expression. At the doses used, both APH and DON repress c-myc expre ssion to approximately the same extent, as well as inducing morphologi c changes in BeWo similar to that of MTX, although neither stimulated hCG alpha expression. Both DON and APH stimulate placental alkaline ph osphatase gene expression, but only MTX and DON stimulate cholesterol side chain cleavage enzyme gene expression. This indicates that the do wnregulation of c-myc gene expression is insufficient to stimulate the expression of all the placental genes stimulated by MTX.