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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 |
Appears in Collections: | Staff Publications Elements |
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