Cytochrome P450 1A2 Metabolizes 17β-Estradiol to Suppress Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect ce...

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Bibliographic Details
Published in:PloS one 2016-04, Vol.11 (4), p.e0153863-e0153863
Main Authors: Ren, Jianwai, Chen, George G, Liu, Yi, Su, Xianwei, Hu, Baoguang, Leung, Billy C S, Wang, Y, Ho, Rocky L K, Yang, Shengli, Lu, Gang, Lee, C G, Lai, Paul B S
Format: Article
Language:English
Subjects:
17β-Estradiol
Angiogenesis
Animal tissues
Animals
Anticancer properties
Apoptosis
Apoptosis - drug effects
Biology and Life Sciences
Cancer
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Cell cycle
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
CYP1A2 protein
Cytochrome
Cytochrome P-450 CYP1A2 - metabolism
Cytochrome P450
Cytotoxicity
Enzymes
Estradiol - analogs & derivatives
Estradiol - metabolism
Estrogen Receptor alpha - metabolism
Estrogen Receptor beta - metabolism
Estrogen receptors
Estrogens
Estrogens - metabolism
Gastroenterology
Gender
Hepatocellular carcinoma
Hepatocytes
Histone deacetylase
Humans
Liver
Liver - drug effects
Liver - metabolism
Liver cancer
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Male
Malignancy
Medical research
Medicine
Medicine and Health Sciences
Metabolism
Metabolites
Mice
Mice, Inbred BALB C
Mice, Nude
Niacinamide - analogs & derivatives
Niacinamide - pharmacology
p53 Protein
Phenylurea Compounds - pharmacology
R&D
Receptors
Receptors, Estrogen - metabolism
Research & development
Research and Analysis Methods
Rodents
Sex hormones
Surgery
Tumor suppressor genes
Tumor Suppressor Protein p53 - metabolism
Xenografts
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Summary:Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect cell proliferation, we sought to investigate if the liver-specific cytochrome P450 1A2 (CYP1A2) mediated the inhibitory effect of estrogen on HCC. In this study, the expression of estrogen-metabolizing enzyme CYP1A2 was determined in HCC tissues and cell lines. Cell proliferation and apoptosis were assessed in cells with or without CYP1A2 overexpression. The levels of 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2-ME) were determined. A xenograft tumor model in mice was established to confirm the findings. It was found that CYP1A2 expression was greatly repressed in HCC. E2 suppressed HCC cell proliferation and xenograft tumor development by inducing apoptosis. The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME. E2 in combination with sorafenib showed an additive effect on HCC. The anti-HCC effect of E2 was not associated with estrogen receptors ERα and ERβ as well as tumor suppressor P53 but enhanced by the approved anti-HCC drug sorafenib. In addition, HDAC inhibitors greatly induced CYP1A2 promoter activities in cancer cells, especially liver cancer cells, but not in non-tumorigenic cells. Collectively, CYP1A2 metabolizes E2 to generate the potent anti-tumor agent 2-ME in HCC. The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0153863