Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19).
Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds-trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)-were found to potently inhibit estrogen biosynthesis (IC50: 1μM and 0.5μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers.
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
Jiajia
J
Guo
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, China.
Yun
Y
Yuan
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
Danfeng
D
Lu
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
Baowen
B
Du
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Liang
L
Xiong
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Jiangong
J
Shi
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
Lijuan
L
Yang
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Wanli
W
Liu
School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, China.
Xiaohong
X
Yuan
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China. Electronic address: zhanggl@cib.ac.cn.
Guolin
G
Zhang
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China. Electronic address: wangfei@cib.ac.cn.
Fei
F
Wang
D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008516:Medicine, Chinese Traditional; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D006109:Poaceae / Q000737:chemistry*; D011494:Protein Kinases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D047072:Aromatase Inhibitors; D001688:Biological Products; D004224:Diterpenes; D004965:Estrogen Antagonists; D004967:Estrogens; D011994:Recombinant Proteins; C000591166:ergosta-6,9,22-triene-3,5,8-triol; D002784:Cholesterol; D000242:Cyclic AMP; D001141:Aromatase; D011494:Protein Kinases; C494251:trans-phytol
Aromatase; Ergosta-6,9,22-triene-3β,5α,8α-triol; Estrogen biosynthesis; Granulosa cells; Phytol; p38 MAPK