Inhibition of cyclic AMP-triggered aromatase gene expression in human choriocarcinoma cells by antisense oligodeoxynucleotide.
Aromatase, an endomembrane-bound cytochrome P450, is the key enzyme of estrogen biosynthesis. Aromatase inhibitors, therefore, are clinically important tools in the treatment of estrogen-dependent tumor growth. To improve the specificity of these tools, inhibition at the nucleic acid level was examined. An antisense oligodeoxynucleotide complementary to the translation start region of human aromatase transcripts (antisense-arom) was synthesized and used to inhibit cyclic AMP-triggered aromatase gene expression in a human choriocarcinoma cell line (JEG-3), both as occurring in an autocrine fashion by secreted human chorionic gonadotropin or as induced by application of the membrane-permeating dibutyryl cyclic AMP. Significant inhibition was obtained in both cases, reaching 70% and 60%, respectively. In addition, the antisense-arom treatment led to accelerated mRNA degradation. The inhibition at the nucleic acid level was accompanied by a decrease of both the aromatase protein and microsomal aromatase activity. The data appear to indicate the antisense strategy to be a most promising approach for the development of a novel type of specific aromatase inhibitor.
Ackermann
K
K
German Cancer Research Center, Heidelberg.
Fauss
J
J
Pyerin
W
W
D001141:Aromatase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D003994:Bucladesine / Q000494:pharmacology; D002822:Choriocarcinoma / Q000201:enzymology* / Q000473:pathology; D006063:Chorionic Gonadotropin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D006063:Chorionic Gonadotropin; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D004958:Estradiol; D003994:Bucladesine; D000242:Cyclic AMP; D001141:Aromatase