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

Ren J, Chen GG, Liu Y, Su X, Hu B, Leung BC, Wang Y, Ho RL, Yang S, Lu G, Lee CG, Lai PB - PLoS ONE (2016)

Bottom Line: The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME.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.The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong; New Territories, Hong Kong, China.

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 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.

No MeSH data available.


Related in: MedlinePlus

CYP1A2 enhanced the inhibitory effect of E2 on xenograft tumors.Empty vector control and CYP1A2-overexpressing Hep3B stable cells were generated and nine clones of each cell line were combined in culture and used in vivo animal experiments. 1 x 107 Hep3B cells with CYP1A2 or empty vector were subcutaneously injected into 4-week old male BALB/c nude mice. Two days later, the mice were intraperitoneally injected with E2 (50 μg/kg) or vehicle control (0.02% DMSO in PBS) once daily for 10 days. Afterwards the mice were maintained for about four weeks before the tumors were collected for analysis. Weights of the tumors were indicated under the tumor images. Three independent xenograft assays were performed. (A) Xenograft tumor-carrying mice and the tumors in each experiment. (B) E2 suppressed the growth of CYP1A2-overexpressing tumors more potently. Mass ratio is expressed as the value of the weight of E2-treated tumors versus the vehicle-treated tumors of each stable cell line (vector or CYP1A2). Each column represents mean±s.d. of data obtained from the three independent xenograft assays. *p<0.05 when compared to vector stable cells.
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pone.0153863.g004: CYP1A2 enhanced the inhibitory effect of E2 on xenograft tumors.Empty vector control and CYP1A2-overexpressing Hep3B stable cells were generated and nine clones of each cell line were combined in culture and used in vivo animal experiments. 1 x 107 Hep3B cells with CYP1A2 or empty vector were subcutaneously injected into 4-week old male BALB/c nude mice. Two days later, the mice were intraperitoneally injected with E2 (50 μg/kg) or vehicle control (0.02% DMSO in PBS) once daily for 10 days. Afterwards the mice were maintained for about four weeks before the tumors were collected for analysis. Weights of the tumors were indicated under the tumor images. Three independent xenograft assays were performed. (A) Xenograft tumor-carrying mice and the tumors in each experiment. (B) E2 suppressed the growth of CYP1A2-overexpressing tumors more potently. Mass ratio is expressed as the value of the weight of E2-treated tumors versus the vehicle-treated tumors of each stable cell line (vector or CYP1A2). Each column represents mean±s.d. of data obtained from the three independent xenograft assays. *p<0.05 when compared to vector stable cells.

Mentions: Having demonstrated that CYP1A2 may metabolite E2 to inhibit the proliferation of cultured HCC cells, an important question to ask is whether this is also the case in vivo. To answer this question, we established xenograft tumors in mice, in which Hep3B cells with stable CYP1A2 overexpression were subcutaneously inoculated. We found that stable cells with either empty vectors or CYP1A2 overexpression could form xenograft tumors at the same rates under normal conditions “vehicle groups, Fig 4A”. E2 treatment led to the reduction in the mass of both cases “E2 groups, Fig 4A”, however E2-mediated reduction of CYP1A2-oeverexpressing tumor was more robust than that of the tumor without CYP1A2 overexpression “Fig 4B, 45% vs 22%, p<0.05”.


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

Ren J, Chen GG, Liu Y, Su X, Hu B, Leung BC, Wang Y, Ho RL, Yang S, Lu G, Lee CG, Lai PB - PLoS ONE (2016)

CYP1A2 enhanced the inhibitory effect of E2 on xenograft tumors.Empty vector control and CYP1A2-overexpressing Hep3B stable cells were generated and nine clones of each cell line were combined in culture and used in vivo animal experiments. 1 x 107 Hep3B cells with CYP1A2 or empty vector were subcutaneously injected into 4-week old male BALB/c nude mice. Two days later, the mice were intraperitoneally injected with E2 (50 μg/kg) or vehicle control (0.02% DMSO in PBS) once daily for 10 days. Afterwards the mice were maintained for about four weeks before the tumors were collected for analysis. Weights of the tumors were indicated under the tumor images. Three independent xenograft assays were performed. (A) Xenograft tumor-carrying mice and the tumors in each experiment. (B) E2 suppressed the growth of CYP1A2-overexpressing tumors more potently. Mass ratio is expressed as the value of the weight of E2-treated tumors versus the vehicle-treated tumors of each stable cell line (vector or CYP1A2). Each column represents mean±s.d. of data obtained from the three independent xenograft assays. *p<0.05 when compared to vector stable cells.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4836701&req=5

pone.0153863.g004: CYP1A2 enhanced the inhibitory effect of E2 on xenograft tumors.Empty vector control and CYP1A2-overexpressing Hep3B stable cells were generated and nine clones of each cell line were combined in culture and used in vivo animal experiments. 1 x 107 Hep3B cells with CYP1A2 or empty vector were subcutaneously injected into 4-week old male BALB/c nude mice. Two days later, the mice were intraperitoneally injected with E2 (50 μg/kg) or vehicle control (0.02% DMSO in PBS) once daily for 10 days. Afterwards the mice were maintained for about four weeks before the tumors were collected for analysis. Weights of the tumors were indicated under the tumor images. Three independent xenograft assays were performed. (A) Xenograft tumor-carrying mice and the tumors in each experiment. (B) E2 suppressed the growth of CYP1A2-overexpressing tumors more potently. Mass ratio is expressed as the value of the weight of E2-treated tumors versus the vehicle-treated tumors of each stable cell line (vector or CYP1A2). Each column represents mean±s.d. of data obtained from the three independent xenograft assays. *p<0.05 when compared to vector stable cells.
Mentions: Having demonstrated that CYP1A2 may metabolite E2 to inhibit the proliferation of cultured HCC cells, an important question to ask is whether this is also the case in vivo. To answer this question, we established xenograft tumors in mice, in which Hep3B cells with stable CYP1A2 overexpression were subcutaneously inoculated. We found that stable cells with either empty vectors or CYP1A2 overexpression could form xenograft tumors at the same rates under normal conditions “vehicle groups, Fig 4A”. E2 treatment led to the reduction in the mass of both cases “E2 groups, Fig 4A”, however E2-mediated reduction of CYP1A2-oeverexpressing tumor was more robust than that of the tumor without CYP1A2 overexpression “Fig 4B, 45% vs 22%, p<0.05”.

Bottom Line: The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME.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.The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong; New Territories, Hong Kong, China.

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 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.

No MeSH data available.


Related in: MedlinePlus