Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0153863
Title: Cytochrome P4501A2 metabolizes 17?-estradiol to suppress hepatocellular carcinoma
Authors: Ren J.
Chen G.G.
Liu Y.
Su X.
Hu B.
Leung B.C.S.
Wang Y.
Ho R.L.K.
Yang S.
Lu G.
Lee C.G. 
Lai P.B.S.
Keywords: 2 methoxyestradiol
catechol methyltransferase
cytochrome P450 1A2
cytochrome P450 3A4
estradiol
protein p53
sorafenib
2-methoxyestradiol
carbanilamide derivative
CYP1A2 protein, human
cytochrome P450 1A2
estradiol
estrogen
estrogen receptor
estrogen receptor alpha
estrogen receptor beta
nicotinamide
protein p53
animal experiment
animal model
animal tissue
apoptosis
Article
cancer growth
cancer incidence
cancer inhibition
cell proliferation
clinical article
concentration (parameters)
controlled study
correlational study
cytotoxicity
female
hormone metabolism
human
human cell
human tissue
liver carcinogenesis
liver cell carcinoma
male
mouse
nonhuman
protein expression
protein function
protein protein interaction
sex difference
upregulation
analogs and derivatives
animal
Bagg albino mouse
Carcinoma, Hepatocellular
drug effects
liver
Liver Neoplasms
metabolism
nude mouse
tumor cell line
Animals
Apoptosis
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Proliferation
Cytochrome P-450 CYP1A2
Estradiol
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogens
Humans
Liver
Liver Neoplasms
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Niacinamide
Phenylurea Compounds
Receptors, Estrogen
Tumor Suppressor Protein p53
Issue Date: 2016
Citation: Ren J., Chen G.G., Liu Y., Su X., Hu B., Leung B.C.S., Wang Y., Ho R.L.K., Yang S., Lu G., Lee C.G., Lai P.B.S. (2016). Cytochrome P4501A2 metabolizes 17?-estradiol to suppress hepatocellular carcinoma. PLoS ONE 11 (4) : e0153863. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0153863
Rights: Attribution 4.0 International
Abstract: 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 17?-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 ER? and ER? 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. © 2016 Ren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161572
ISSN: 19326203
DOI: 10.1371/journal.pone.0153863
Rights: Attribution 4.0 International
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