EFFECTS OF HYDROXYUREA AND CYCLIC ADENOSINE-MONOPHOSPHATE PROTEIN KINASE-A INHIBITORS ON THE EXPRESSION OF THE HUMAN CHORIONIC-GONADOTROPIN ALPHA-SUBUNIT AND C-MYC GENES IN CHORIOCARCINOMA

We have previously shown that treatment of choriocarcinoma cells with methotrexate or hydroxyurea leads to both cessation of cell growth, accompanied by repression of c-myc oncogene expression, and induction of genes associated with the placental phenotype, including both subunits of human chorionic gonadotropin (hCG) and placental alkaline phosphatase. Since the genes induced by these antimetabolites are also cyclic AMP inducible, we hypothesized that these antimetabolites may cause activation of the cyclic AMP/protein kinase A pathway, suppressing genes associated with cellular proliferation and inducing placental gene expression. Three inhibitors of the cyclic AMP/protein kinase A pathway were assayed for their ability to inhibit the induction of the human chorionic gonadotropin alpha gene by hydroxyurea, and none of these inhibitors eliminated this induction. In addition, blockade of the cyclic AMP/protein kinase A pathway did not reverse the suppression of c-myc by hydroxyurea. The results of the inhibitor studies suggest that hydroxyurea acts independently of the protein kinase A pathway to stimulate gene expression, and that suppression of c-myc is insufficient to cause the induction of the human chorionic gonadotropin alpha gene by hydroxyurea.