Regulation of gene expression in choriocarcinoma by methotrexate and hydroxyurea.
Choriocarcinoma, a highly malignant neoplasm of trophoblastic origin, is remarkable for its marked degree of sensitivity to chemotherapeutic agents. We treated two cell lines derived from choriocarcinoma patients with two antineoplastic agents, methotrexate and hydroxyurea (HU), both of which cause nucleotide depletion and have been previously shown to be effective against choriocarcinoma, and found pleiotropic regulation of several genes. Three genes, hCG alpha-subunit, beta-subunit, and placental alkaline phosphatase, were all strongly induced by methotrexate and HU. Expression of c-myc, an oncogene associated with proliferation, was reduced to nearly undetectable levels by the drug treatment, while expression of beta 2-microglobulin, a component of the class 1 major histocompatibility locus, was unchanged. In addition, the mechanism of induction by HU of one of these genes, the hCG alpha-subunit gene, was found to occur at the level of transcription. The similar effects of methotrexate and HU, two mechanistically unrelated antimetabolites, on the induction of specific gene expression in choriocarcinoma cells suggest that these effects are due to nucleotide pool alteration, rather than specific ligand effects. Furthermore, the hCG alpha-subunit promoter contains a transcriptionally regulated HU-responsive element.
Arbiser
J L
JL
Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115.
Arbiser
Z K
ZK
Majzoub
J A
JA
D002822:Choriocarcinoma / Q000235:genetics*; D006063:Chorionic Gonadotropin / Q000235:genetics; D004247:DNA / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D008727:Methotrexate / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D006063:Chorionic Gonadotropin; D011506:Proteins; D012333:RNA, Messenger; C055324:phospholipase A2-activating protein; D004247:DNA; D006918:Hydroxyurea; D008727:Methotrexate