Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N-(4-hydroxy-phenyl)-retinamide.
The effect of the chemopreventive synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4-HPR) on aromatase activity and expression was examined. 4-HPR caused a dose-dependent inhibition of aromatase activity in microsomes isolated from JEG-3 human placental carcinoma cells. The kinetics of inhibition were analysed by double-reciprocal plot. The Km of the substrate increased and the Vmax of the reaction decreased in the presence of 4-HPR, indicating that enzyme inhibition involved both competition for the substrate-binding site and non-competitive mechanisms. To determine whether 4-HPR would also inhibit aromatase activity in intact cells, MCF-7 human breast cancer cells were incubated with or without cAMP in the presence of 4-HPR. 4-HPR inhibited both basal and cAMP-induced aromatase activity in intact MCF-7 cells. The induction of aromatase mRNA expression in MCF-7 cells by cAMP was inhibited in cells treated with 4-HPR. These results indicate that 4-HPR inhibits both the enzymatic activity and expression of aromatase. These activities may play an important role in the known chemopreventive effect of 4-HPR towards breast cancer.
Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21701-1201, USA.
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Ciolino
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Wang
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Sathyamoorthy
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001141:Aromatase / Q000235:genetics; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008861:Microsomes / Q000201:enzymology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D016588:Anticarcinogenic Agents; D047072:Aromatase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017313:Fenretinide; D001141:Aromatase