Role of AhR in positive regulation of cell proliferation and survival

Yin, Jiuheng; Sheng, Baifa; Qiu, Yuan; Yang, Kunqiu; Xiao, Weidong; Yang, Hua

doi:10.1111/cpr.12282

Cited by 67 publications

(59 citation statements)

References 76 publications

(87 reference statements)

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“…AHR knockdown inhibits the growth of cancer cells. AHR is highly expressed in a wide panel of tumors and previous studies indicated that overexpression of AHR could help cancer cells survive under cellular stress (34,35). To address whether AHR imparts survival to cancer cells, AHR was knocked down in a variety of cell lines including human ovarian cancer cell line (A2780), human lung cancer cell line (A549), human breast cancer cell line (MDA-MB231), human hepatocellular carcinoma cell line (Bel7402), human colon cancer cell line (HCT-8 and SW620) and human embryonic kidney 293 cells (HEK293).…”

Section: Resultsmentioning

confidence: 99%

Paclitaxel-mediated human aryl hydrocarbon receptor mRNA translation by an internal ribosomal entry site-dependent mechanism

Gao

Sun

et al. 2017

Oncology Reports

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known in mediating the toxicities of dioxins and dioxin-like compounds. AHR is activated by a variety of endogenous ligands and participating in tumor development. Thus, it will provide a new approach for cancer prevention and treatment to study the translation mechanism of AHR in tumor cells. In this study, we show that the 5'-untranslated region (UTR) of AHR mRNA contains an internal ribosome entry site (IRES). After mapping the entire AHR 5'-UTR, we determined that the full-length 5'-UTR is indispensable for the highest IRES activity. Interestingly, we found that AHR expression is induced in ovarian (A2780), breast (MDA-MB231), hepatic (Bel7402) and colorectal cancer cells (SW620) by chemotherapeutic drug paclitaxel (PTX) through IRES-dependent translation mechanism. Moreover, IRES activity is increased in the PTX-resistant ovarian cancer cells in which AHR protein expression was also enhanced. These results strongly suggest an important role for AHR IRES-dependent translation mechanism in cancer cell response to paclitaxel treatment.

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Section: Resultsmentioning

confidence: 99%

Paclitaxel-mediated human aryl hydrocarbon receptor mRNA translation by an internal ribosomal entry site-dependent mechanism

Gao

Sun

et al. 2017

Oncology Reports

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“…The AhR is a nuclear transcription factor that mediates toxic responses by adjusting numbers of metabolism-related enzymes, including CYP1A1. The AhR binds to the AhR nuclear translocator (ARNT) and the ligand-bound AhR/ARNT complex translocates from the cytoplasm into the nucleus to modulate the expression of target genes, such as CYP1A1 and CYP1B1 [ 14 ]. IS inhibited the expression of fetuin-A through AhR activation in a human hepatoma HepG2 cell line [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

Wakamatsu

Yamamoto

Ito

et al. 2018

Toxins

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In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients.

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“…When ligand bound, conformational changes allow AHR to dissociate from the cytoplasmic complex and bind to a cofactor, aryl hydrocarbon nuclear translocator (ARNT, also called HIF-1B), and together these proteins translocate to the nucleus and bind AHR-response elements in the promoters of target genes [ 4 , 5 ]. While the AHR has many transcriptional targets, the two best characterized are the cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1) genes [ 6 ]. These enzymes belong to the CYP1 family of monoxygenases, and are responsible for the metabolism of a variety of endogenous and xenobiotic molecules into bioactive compounds and toxic derivatives, respectively.…”

Section: Introductionmentioning

confidence: 99%

Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs)

et al. 2017

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The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor conserved across phyla from flies to humans. Activated by a number of endogenous ligands and environmental toxins, studies on AHR function and gene regulation have largely focused on a toxicological perspective relating to aromatic hydrocarbons generated by human activities and the often-deleterious effects of exposure on vertebrates mediated by AHR activation. A growing body of work has highlighted the importance of AHR in physiologic processes, including immune cell differentiation and vascular patterning. Here we dissect the contribution of the 3 zebrafish AHRs, ahr1a, ahr1b and ahr2, to endothelial cyp1a1/b1 gene regulation under physiologic conditions and upon exposure to the AHR ligand Beta-naphthoflavone. We show that in fish multiple AHRs are functional in the vasculature, with vessel-specific differences in the ability of ahr1b to compensate for the loss of ahr2 to maintain AHR signaling. We further provide evidence that AHR can regulate the expression of the chemokine receptor cxcr4a in endothelial cells, a regulatory mechanism that may provide insight into AHR function in the endothelium.

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Role of AhR in positive regulation of cell proliferation and survival

Cited by 67 publications

References 76 publications

Paclitaxel-mediated human aryl hydrocarbon receptor mRNA translation by an internal ribosomal entry site-dependent mechanism

Paclitaxel-mediated human aryl hydrocarbon receptor mRNA translation by an internal ribosomal entry site-dependent mechanism

Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs)

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