A remarkable new target gene for the dioxin receptor

Fernandez-Salguero, Pedro

doi:10.4161/cam.4.2.10387

Cited by 26 publications

(7 citation statements)

References 38 publications

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“…A second plausible mechanism is indirect regulation of invasion genes through TGF-β, previously shown to be regulated by the AHR [ 6 , 113 , 114 ] and to regulate invasion-associated genes including MMP2 and MMP9 [ 115 ]. Several other factors, including epiregulin [ 116 ], VAV3 [ 117 , 118 ], and AP1 [ 61 ] are AHR responsive and also may play a role in altering cell adhesion, motility and metastasis [ 104 , 118 , 119 , 120 ]. These possibilities are currently being tested.…”

Section: Discussionmentioning

confidence: 99%

Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor

Narasimhan

Zulick

Novikov

et al. 2018

IJMS

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We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER−/PR−/Her2− and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor

Narasimhan

Zulick

Novikov

et al. 2018

IJMS

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“…The role that the AHR plays in cytoskeletal organization and migratory ability remains unclear, but evidence has shown that AHR null fibroblasts have lower migration due to deregulated cytoskeletons, and treatment of cells with AHR ligands results in a decrease in cell-cell contact and an increase in cell-extracellular matrix contact (43, 44). One potential pathway through which these changes could occur is the AHR-mediated regulation of VAV3, which is itself a mediator of Rho GTPases and downstream cytoskeletal organization (45, 46). Clearly, the targets of AHR antagonism in HNSCC cells will need to be explored.…”

Section: Discussionmentioning

confidence: 99%

Ah Receptor Antagonism Represses Head and Neck Tumor Cell Aggressive Phenotype

DiNatale

Smith

John

et al. 2012

Molecular Cancer Research

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The aryl hydrocarbon receptor (AHR) has been shown to play a role in an increasing number of cellular processes. Recent reports have linked the AHR to cell proliferation, cytoskeletal arrangement, and tumor invasiveness in various tumor cell types. The AHR plays a role in the de-repression of the IL6 promoter in certain tumor cell lines, allowing for increased transcriptional activation by cytokines. Here, we show that there is a significant level of constitutive activation of the AHR in cells isolated from head and neck squamous cell carcinoma (HNSCC) patients. Constitutive activation of the AHR in HNSCC cells was blocked by antagonist treatment, leading to a reduction in IL6 expression. Additionally, the AHR exhibits a high level of expression in HNSCC cells compared to normal keratinocytes. These findings led to the hypothesis that the basal AHR activity in HNSCC cells plays a role in the aggressive phenotype of these tumors, and that antagonist treatment could mitigate this phenotype. This study provides evidence that antagonism of the AHR in HNSCC tumor cells, in the absence of exogenous receptor ligands, has a significant effect on tumor cell phenotype. Treatment of these cell lines with the AHR antagonists 6, 2′, 4′-trimethoxyflavone, or the more potent GNF351, decreased migration, and invasion of HNSCC cells and prevented benzo[a]pyrene-mediated induction of the chemotherapy efflux protein ABCG2. Thus, an AHR antagonist treatment has been shown to have therapeutic potential in HNSCC through a reduction in aggressive cell phenotype.

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“…Thus, AHR activation, whether arising from a loss of cell adhesion or agonist stimulation, may promote metastasis. A number of pro-migratory factors appear to be impacted by AHR, including adhesion components 75 , proteases 74 , cytokines 76 , signal transduction adaptors 77, 78 and transcription factors 79, 80 . In contrast, expression of the chemokine CXCR4 is down regulated by AHR agonist mediated activity in breast cancer cells, suggesting an anti-metastatic effect of AHR activation 81, 82 .…”

Section: Consequences Of Ahr Activation In Cancermentioning

confidence: 99%

“…AHR-dependent expression of matrix metalloproteases (MMPs) and intra-cellular signaling factors, which promote cytoskeletal rearrangement (e.g. VAV3) render tumor cells increasingly motile 78 . The presence of tumor-associated inflammatory cytokine signaling results in a self-sustaining synergistic loop in combination with AHR activation, which enhances cell motility 18 .…”

Section: Key Pointsmentioning

confidence: 99%