Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

Kolluri, Siva Kumar; Jin, Un Ho; Safe, Stephen

doi:10.1007/s00204-017-1981-2

Cited by 133 publications

(100 citation statements)

References 170 publications

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“…TCDD promotes cell proliferation such as breast cancer stem cells (40) and hepatic stem cells (29) via AHR-dependent pathway, indicating that AHR may be a potential target for cancer chemotherapy (41). AHR is involved in various aspects of cardiovascular homeostasis and diseases, including cardiomyocyte differentiation in embryonic development (42), angiotensin II release from endothelial cells in hypertension (43), and vascular remodeling in placenta (44).…”

Section: Discussionmentioning

confidence: 99%

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

et al. 2019

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ABSTRACT2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) is an environmental pollutant that causes cardiovascular toxicity. The phenotypic transformation of vascular smooth muscle cells (VSMCs) from the contractile to the synthetic phenotype is a hallmark of vascular response to injury. However, the precise role and molecular mechanism of TCDD in vascular remodeling remains unknown. In the present study, we found that TCDD treatment promoted VSMC phenotypic transition from contractile to synthetic phenotype and exaggerated vascular neointimal hyperplasia after wire injury in mice. TCDD treatment enhanced VSMC entry into cell cycle from G0/G1 phase to S and G2/M phase. The expression of cyclin D1, cyclin‐dependent kinase 4 (CDK4), and its phosphorylation were coordinately increased in response to TCDD treatment. Knocking down of aryl hydrocarbon receptor (AHR) inhibited VSMC phenotypic transition induced by TCDD and promoted S/G2 phase cell cycle arrest. TCDD treatment markedly increased oncogenic c‐Jun gene expression in VSMCs. ChIP assay revealed the direct binding of AHR on the promoter of c‐Jun to up‐regulate the mRNA expression of c‐Jun. Silencing of c‐Jun gene enhanced the expression of p53 and p21, whereas attenuated the expression of CDK4 and cyclin D1 leading to the decrease in the TCDD‐stimulated VSMC proliferation and synthetic phenotype transition in vitro. In vivo study showed that genetic ablation of c‐Jun in VSMCs restricted injury‐induced neointimal hyperplasia in TCDD‐treated mice. Thus, TCDD exposure exaggerated injury‐induced vascular remodeling by the activation of AHR and up‐regulation of the expression of its target gene c‐Jun, indicating that inhibition of AHR may be a promising prevention strategy for TCDD‐associated cardiovascular diseases.—Guo, S., Zhang, R., Liu, Q., Wan, Q., Wang, Y., Yu, Y., Liu, G., Shen, Y., Yu, Y., Zhang, J. 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice. FASEB J. 33, 10207–10217 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

et al. 2019

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“…The aryl hydrocarbon receptor (AhR) belongs to the family of basic helix‐loop‐helix transcription factors and is known to mediate the effects of polycyclic and polyhalogenated aromatic hydrocarbon ligands, including environmental toxins such as benzo[ a ]pyrene ( 1 ) and 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin ( 2 ) . Multiple other ligands, including bilirubin, prostaglandins, tryptophan, and even plant‐derived ligands such as resveratrol and flavones also exist .…”

Section: Introductionmentioning

confidence: 99%

“…(2). [5][6][7][8][9] Multiple other ligands, including bilirubin, prostaglandins, tryptophan, and even plant-derived ligands such as resveratrol and flavones also exist. [10,11] Ongoing analysiso fA hR functioni sr evealing the increased complexity of this pathway, with evidence that the AhR has the ability to modulate gene transcription and other cellular events without ligand activation.…”

Section: Introductionmentioning

confidence: 99%

Dichlorophenylacrylonitriles as AhR Ligands That Display Selective Breast Cancer Cytotoxicity in vitro

et al. 2018

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Knoevenagel condensation of 3,4-dichloro- and 2,6-dichlorophenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (5) and (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (6) displayed 0.56±0.03 and 0.127±0.04 μm growth inhibition (GI ) and 260-fold selectivity for the MCF-7 breast cancer cell line. A 2,6-dichlorophenyl moiety saw a 10-fold decrease in potency; additional nitrogen moieties (-NO ) enhanced activity (Z)-2-(2,6-dichloro-3-nitrophenyl)-3-(2-nitrophenyl)acrylonitrile (26) and (Z)-2-(2,6-dichloro-3-nitrophenyl)-3-(3-nitrophenyl)acrylonitrile (27), with the corresponding -NH analogues (Z)-2-(3-amino-2,6-dichlorophenyl)-3-(2-aminophenyl)acrylonitrile (29) and (Z)-2-(3-amino-2,6-dichlorophenyl)-3-(3-aminophenyl)acrylonitrile (30) being more potent. Despite this, both 29 (2.8±0.03 μm) and 30 (2.8±0.03 μm) were found to be 10-fold less cytotoxic than 6. A bromine moiety effected a 3-fold enhancement in solubility with (Z)-3-(5-bromo-1H-pyrrol-2-yl)-2-(3,4-dichlorophenyl)acrylonitrile 18 relative to 5 at 211 μg mL . Modeling-guided synthesis saw the introduction of 4-aminophenyl substituents (Z)-3-(4-aminophenyl)-2-(3,4-dichlorophenyl)acrylonitrile (35) and (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide (38), with respective GI values of 0.030±0.014 and 0.034±0.01 μm. Other analogues such as 35 and 36 were found to have sub-micromolar potency against our panel of cancer cell lines (HT29, colon; U87 and SJ-G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2-C, neuroblastoma; MIA, pancreas; and SMA, murine glioblastoma), except compound 38 against the U87 cell line. A more extensive evaluation of 38 ((Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide) in a panel of drug-resistant breast carcinoma cell lines showed 10-206 nm potency against MDAMB468, T47D, ZR-75-1, SKBR3, and BT474. Molecular Operating Environment docking scores showed a good correlation between predicted binding efficiencies and observed MCF-7 cytotoxicity. This supports the use of this model in the development of breast-cancer-specific drugs.

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“…Benzo[α]pyrene (BaP) is one of the major compounds of the PAH family that can be found at high levels in cigarette smoke (Schneider, Roller, Kalberlah, & Schuhmacher‐Wolz, ). Studies have shown that BaP acts as an exogenous ligand for aryl hydrocarbon receptor (AhR) (Kolluri, Jin, & Safe, ). AhR is a transcription factor of Per‐ARNT‐Sim‐basic‐helix‐loop‐helix (PAS‐bHLH) family proteins.…”

Section: Introductionmentioning

confidence: 99%

“…exogenous ligand for aryl hydrocarbon receptor (AhR) (Kolluri, Jin, & Safe, 2017). AhR is a transcription factor of Per-ARNT-Sim-basichelix-loop-helix (PAS-bHLH) family proteins.…”

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confidence: 99%

Invasion and migration of MDA‐MB‐231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/β4 integrin signaling

Shadboorestan

Tarfiei

Montazeri

et al. 2018

J of Applied Toxicology

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Benzo[α]pyrene (BaP) can have significant role in the development of breast cancer via aryl hydrocarbon receptor (AhR) activation. AhR activation has been studied in several functions such as survival, migration and invasion of cancer cells. In cancer, integrins contribute to the migration/invasion process and are regulated by nuclear factor of activated T cells (NFAT) and transforming growth factor (TGF) beta pathways. The aim of the present study was to examine the effect of BaP, an activator of AhR and cyclosporine A (CsA), as inhibitor of NFAT on migration and invasion of MDA‐MB‐231 cells. Furthermore, the effects of BaP and CsA were evaluated regarding the crosstalk of AhR, NFAT1 and TGF‐β receptor 1 signaling. Treatment of MDA‐MB‐231 with BaP resulted in significantly more live cells in low doses; however, blocking NFAT with CsA decreased the viability of the cells. Activation of AhR by BaP induced invasion as well as migration in MDA‐MB‐231 cells, which was blocked by AhR antagonist. Unlike BaP, block of NFAT with CsA inhibited cell migration and cell invasion. In these cells, BaP significantly reduced AhR expression while this reduction was reversed by CH‐223191; however, CsA treatment lowered the AhR expression only at low dose. The level of β4 integrin was significantly reduced by CsA at 1 and 2.5 μm. Protein levels of Snail and TGF‐β receptor 1 were not significantly altered by BaP and CsA treatments. Considering these findings, the low AhR expression and high β4 integrin level following BaP and/or CsA treatments may contribute to the higher invasion/migration in MDA‐MB‐231 cells.

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Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

Cited by 133 publications

References 170 publications

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

Dichlorophenylacrylonitriles as AhR Ligands That Display Selective Breast Cancer Cytotoxicity in vitro

Invasion and migration of MDA‐MB‐231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/β4 integrin signaling

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