Cytochrome P450 1A2 Metabolizes 17 beta-Estradiol to Suppress Hepatocellular Carcinoma
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AbstractHepatocellular 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 beta-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 alpha and ER beta 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.
All Author(s) ListRen JW, Chen GG, Liu Y, Su XW, Hu BG, Leung BCS, Wang Y, Ho RLK, Yang SL, Lu G, Lee CG, Lai PBS
Journal namePLoS ONE
Year2016
Month4
Day19
Volume Number11
Issue Number4
PublisherPUBLIC LIBRARY SCIENCE
ISSN1932-6203
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesMultidisciplinary Sciences; Science & Technology - Other Topics

Last updated on 2020-14-10 at 00:30