Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells

Portaz, Ana Clara de Tomaso; Caimi, Giselle Romero; Sánchez, Marcela; Chiappini, Florencia; Randi, Andrea; Pisarev, Diana L. Kleiman de; Álvarez, Laura

doi:10.1016/j.tox.2015.07.013

Cited by 28 publications

(27 citation statements)

References 30 publications

(30 reference statements)

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“…The ERK signaling pathway is important for tumor cell proliferation through regulating the cell cycle (30). ERK can facilitate cancer cell growth by promoting cell movement from the G1 phase to the S phase (31). The current results exhibited that baicalein blocked HeLa cells in G0/G1 phase, and U0126 also decreased cell content in S phase.…”

Section: Discussionsupporting

confidence: 51%

The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa

Zhang

Wang

et al. 2017

Molecular Medicine Reports

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To explore the restraining effect of baicalein and the mitogen-activation protein kinase kinase inhibitor, U0126, on human cervical cell line HeLa proliferation, apoptosis and migration. HeLa cells were treated by different concentrations of baicalein or U0126. A Cell Counting Kit (CCK)‑8 assay was applied to examine cell viability. Flow cytometry was used to determine cell cycle and apoptosis. A wound healing assay was performed to detect cell migration. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was adopted to test cell apoptosis. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis was used to detect apoptosis gene and protein expression. CCK‑8 assay demonstrated that baicalein and U0126 suppressed HeLa cell viability by dose dependence. TUNEL, Annexin V‑fluorescein isothiocyanate/propidium iodide, and ratio of Bcl‑2‑associated X protein and B cell lymphoma 2 indicated that baicalein and U0126 induced HeLa cell apoptosis. Flow cytometry revealed that baicalein blocked the cell cycle of HeLa in G0/G1 phase. A wound healing assay demonstrated that baicalein significantly inhibited HeLa cell migration compared with control. Baicalein and U0126 markedly downregulated extracellular signal‑regulated kinase 1/2, matrix metalloproteinase (MMP) 2 and MMP9 levels both in mRNA and protein. In the present study, the authors demonstrated that baicalein and U0126 may be used in cervical cancer treatment by inhibiting cell migration and inducing cell apoptosis.

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Section: Discussionsupporting

confidence: 51%

The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa

Zhang

Wang

et al. 2017

Molecular Medicine Reports

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“…VD is implicated to play key roles in the control of cell proliferation (Samuel and Sitrin, 2008). Besides, the HCB carcinogenic effect appears to be related to the increase of cell proliferation and subsequent loss of the balance between proliferation and apoptosis in the liver (Giribaldi et al, 2011;Portaz et al, 2015). In the present study, the hepatocyte proliferation (Ki-67) was significantly higher in all DEN/HCB-treated groups than the untreated group (p < 0.001) ( Fig.…”

Section: Vd 3 Supplementation Reduces Hepatocyte Proliferationsupporting

confidence: 50%

“…In the early stages of DEN/HCB-induced hepatocarcinogenesis model, the altered hepatic microenvironment associated with increased oxidative stress and cell proliferation favors the development of preneoplastic AHF (Almeida et al, 1997;Giribaldi et al, 2011;Portaz et al, 2015) (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

“…Experimentally, HCB showed to promote the development of hepatocellular preneoplastic (PNL) and neoplastic lesions in both carcinogen-initiated and non-initiated rodents (Stewart et al, 1989;Carthew and Smith, 1994;Gustafson et al, 2000). This carcinogenic effect seems to be associated to an increase in cell proliferation and subsequent loss of the homeostatic balance between cell proliferation and death in rodent liver (Giribaldi et al, 2011;Portaz et al, 2015). In addition, HCB showed to increase oxidative stress in rodent liver by reducing antioxidant enzyme activity (Almeida et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, HCB showed to increase oxidative stress in rodent liver by reducing antioxidant enzyme activity (Almeida et al, 1997). For these reasons, HCB is usually used as a classical promoting agent in chemically-induced rodent models of hepatocarcinogenesis (Gustafson et al, 2000;Portaz et al, 2015). In these models, the altered hepatocyte foci (AHF), considered as hepatocellular PNL, are easily identified and quantified in short and medium-term bioassays, allowing the investigation of potential modifying factors on early stage of hepatocarcinogenesis, including dietary micronutrients (Klaunig and Kamendulis, 1999;Ogawa, 2009;Romualdo et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Vitamin D3 supplementation attenuates the early stage of mouse hepatocarcinogenesis promoted by hexachlorobenzene fungicide

Romualdo

Goto

Fernandes

et al. 2017

Food and Chemical Toxicology

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Hexachlorobezene (HCB), a fungicide widely distributed in the environment, promotes the development of hepatocellular preneoplastic lesions (PNL) and tumors in rodents. In contrast, vitamin D (VD) supplementation presents a potential role for the prevention/treatment of chronic liver diseases. Thus, we investigated whether VD supplementation attenuates the early stage of HCB-promoted hepatocarcinogenesis. Female Balb/C mice were injected a single dose of diethylnitrosamine (DEN, 50 mg/kg) at postnatal day 15. From day 40 onwards, mice were fed with a standard diet containing 0.02% HCB alone or supplemented with VD (10,000 or 20,000 IU/Kg diet) for 20 weeks. Untreated mice were fed just standard diet. After this period, mice were euthanized and liver and serum samples were collected. Compared to the untreated group, DEN/HCB treatment decreased total hepatic glutathione levels and glutathione peroxidase (GSH-Px) activity while increased lipid peroxidation, p65 protein expression, cell proliferation/apoptosis and the PNL development. In contrast, dietary VD supplementation enhanced vitamin D receptor (VDR) protein expression, total glutathione levels and GSH-Px activity while diminished lipid hydroperoxide levels. Also, VD supplementation decreased p65 protein expression, hepatocyte proliferation, the size and the liver area occupied by PNL. Therefore, our findings indicate that VD supplementation attenuates the early stage of HCB-promoted hepatocarcinogenesis.

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EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

et al. 2016

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Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS‐FLI1. We report that EWS‐FLI1 suppresses TDO2‐mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS‐FLI1‐dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS‐FLI1, resulting in kynurenine and kynurenic acid accumulation, both aryl hydrocarbon receptor (AHR) ligands. Activated AHR binds to the promoter region of target genes. We demonstrate that EWS‐FLI1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS‐FLI1 suppresses autocrine AHR signaling by inhibiting TDO2‐catalyzed TRP breakdown.

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Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells

Cited by 28 publications

References 30 publications

The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa

The restraining effect of baicalein and U0126 on human cervical cancer cell line HeLa

Vitamin D3 supplementation attenuates the early stage of mouse hepatocarcinogenesis promoted by hexachlorobenzene fungicide

EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

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