Intersection of AHR and Wnt Signaling in Development, Health, and Disease

Schneider, Andrew J.; Branam, Amanda M.; Peterson, Richard E.

doi:10.3390/ijms151017852

Cited by 89 publications

(80 citation statements)

References 188 publications

(311 reference statements)

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“…In addition, it has been shown that phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays a role in the regulation of several genes in carcinogenesis such as β-Catenin, p21, p27, Mdm2 or Forkhead transcription factors [13]. Importantly, these CSC-regulating pathways have been shown to crosstalk with several transcription factors and signaling pathways such as the aryl hydrocarbon receptor (AhR) [14]. …”

Section: Introductionmentioning

confidence: 99%

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

2017

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BackgroundBreast cancer stem cells (CSCs) are small sub-type of the whole cancer cells that drive tumor initiation, progression and metastasis. Recent studies have demonstrated a role for the aryl hydrocarbon receptor (AhR)/cytochrome P4501A1 pathway in CSCs expansion. However, the exact molecular mechanisms remain unclear.MethodsThe current study was designed to a) determine the effect of AhR activation and inhibition on breast CSCs development, maintenance, self-renewal, and chemoresistance at the in vitro and in vivo levels and b) explore the role of β-Catenin, PI3K/Akt, and PTEN signaling pathways. To test this hypothesis, CSC characteristics of five human breast cancer cells; SKBR-3, MCF-7, and MDA-MB231, HS587T, and T47D treated with AhR activators or inhibitor were determined using Aldefluor assay, side population, and mammosphere formation. The mRNA, protein expression, cellular content and localization of the target genes were determined by RT-PCR, Western blot analysis, and Immunofluorescence, respectively. At the in vivo level, female Balb/c mice were treated with AhR/CYP1A1 inducer and histopathology changes and Immunohistochemistry examination for target proteins were determined.ResultsThe constitutive mRNA expression and cellular content of CYP1A1 and CYP1B1, AhR-regulated genes, were markedly higher in CSCs more than differentiating non-CSCs of five different human breast cancer cells. Activation of AhR/CYP1A1 in MCF-7 cells by TCDD and DMBA, strong AhR activators, significantly increased CSC-specific markers, mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and percentage of side population (SP) cells, whereas inactivation of AhR/CYP1A1 using chemical inhibitor, α-naphthoflavone (α-NF), or by genetic shRNA knockdown, significantly inhibited the upregulation of ALDH activity and SP cells. Importantly, inactivation of the AhR/CYP1A1 significantly increased sensitization of CSCs to the chemotherapeutic agent doxorubicin. Mechanistically, Induction of AhR/CYP1A1 by TCDD and DMBA was associated with significant increase in β-Catenin mRNA and protein expression, nuclear translocation and its downstream target Cyclin D1, whereas AhR or CYP1A1 knockdown using shRNA dramatically inhibited β-Catenin cellular content and nuclear translocation. This was associated with significant inhibition of PTEN and induction of total and phosphorylated Akt protein expressions. Importantly, inhibition of PI3K/Akt pathway by LY294002 completely blocked the TCDD-induced SP cells expansion. In vivo, IHC staining of mammary gland structures of untreated and DMBA (30 mg/kg, IP)- treated mice, showed tremendous inhibition of PTEN expression accompanied with an increase in the expression p-Akt, β-Catenin and stem cells marker ALDH1.ConclusionsThe present study provides the first evidence that AhR/CYP1A1 signaling pathway is controlling breast CSCs proliferation, development, self-renewal and chemoresistance through inhibition of the PTEN and activation of β-Catenin and Akt pathways.

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Section: Introductionmentioning

confidence: 99%

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

2017

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“…Wnt stabilizes cytosolic beta-catenin, which then binds to TCF/LEF-1 in the nucleus and recruits transcription factors Brg1 and CREB-binding protein to initiate Wnt-targeted gene expression [6]. Wnt signaling has been proven to be associated with embryonic development [6], tissue renewal and regeneration [10], and various cancer pathologies [11], such as cell proliferation, cell cycle, cell death, and cell invasion/migration [12].…”

Section: Discussionmentioning

confidence: 99%

“…The pathway activates downstream targets and thereby regulates many biological processes through a complex of beta-catenin and the T-cell factor/ lymphoid-enhancer factor 1 (TCF/LEF-1) family. Wnt stabilizes cytosolic beta-catenin, which then binds to TCF/LEF-1 in the nucleus and recruits transcription factors Brg1 and CREB-binding protein to initiate Wnttargeted gene expression [6]. SFRP1, a member of the secreted frizzled-related protein (SFRP) family of Wnt inhibitors, can limit canonical and noncanonical Wnt signaling, binding the Wnt ligand and sequestering it away from Fz receptors.…”

Section: Introductionmentioning

confidence: 99%

MiR-27a regulates Wnt/beta-catenin signaling through targeting SFRP1 in glioma

Wang

Xie²,

Xie³

et al. 2015

NeuroReport

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Glioma is one of the most common intracranial tumors, and the prognosis is poor, although more and more treatments are employed. Wnt/beta-catenin signaling has been reported to be associated with glioma. SFRP1 acts as an antagonist and inhibits Wnt signaling by binding to Wnt molecules. In the present study, we aimed to investigate miRNA-27a as an antineoplastic factor that inhibits the Wnt/beta-catenin pathway by binding to the SFRP1 3'-UTR in glioma in vitro. We first showed that the expression of miR-27a was elevated in both glioma samples and cell lines. Furthermore, downregulation of miR-27a induced growth inhibition, cycle arrest, and apoptosis, and suppressed invasion/migration in glioma cell lines. Quantitative real-time PCR, western blot, and luciferase assay analysis showed that SFRP1 is a direct target of miR-27a. Overexpression of SFRP1 inhibited the malignancy of glioma cell lines. Our investigation showed that downregulation of miR-27a suppressed beta-catenin/TCF-4 transcription activity by targeting SFRP1. Our findings identify a role for miR-27a in glioma cell viability, cycle, apoptosis, and invasion/migration after activation of Wnt/beta-catenin signaling through SFRP1.

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“…However, the molecular mechanisms behind the effects are still poorly known. Recently, studies have begun to point to an AHR-dependent dysregulation of Wnt/β-catenin signaling as a potential mechanism (Schneider et al , 2014a). …”

Section: Introductionmentioning

confidence: 99%

Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

Wincent

Stegeman

Jönsson

2015

Toxicology and Applied Pharmacology

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Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholine-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

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Intersection of AHR and Wnt Signaling in Development, Health, and Disease

Cited by 89 publications

References 188 publications

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

MiR-27a regulates Wnt/beta-catenin signaling through targeting SFRP1 in glioma

Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

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