TCDD-induced activation of aryl hydrocarbon receptor regulates the skin stem cell population

Mandavia, Chirag

doi:10.1016/j.mehy.2014.12.023

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…This type of bioenergetic profile contrasts with the aerobic glycolysis Warburg effect exhibited by cancer stem cells (24) and is therefore consistent with a suppression of stemness (Fig. This is consistent with the effect of TCDD on skin stem cell turnover (18). This finding was corroborated by flow cytometry studies conducted in parallel, in which TCDD-treated cells exhibited a significant (48%) reduction (P Ͻ 0.05, n ϭ 4) in the number of GFP ϩ stem cells compared with control (data not shown).…”

Section: Tcdd Treatment Suppresses the Stem Cell Metabolic Phenotypesupporting

confidence: 82%

A bioassay to measure energy metabolism in mouse colonic crypts, organoids, and sorted stem cells

Yang

Davidson

Callaway

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Evidence suggests that targeting cancer cell energy metabolism might be an effective therapeutic approach for selective ablation of malignancies. Using a Seahorse Extracellular Flux Analyzer, we have demonstrated that select environmental agents can alter colonic mitochondrial function by increasing respiration-induced proton leak, thereby inducing apoptosis, a marker of colon cancer risk. To further probe bioenergetics in primary intestinal cells, we developed methodology that can be modified and adapted to measure the bioenergetic profiles of colonic crypts, the basic functional unit of the colon, and colonic organoids, an ex vivo 3D culture of colonic crypts. Furthermore, in combination with the MoFlo Astrios High-Speed Cell Sorter, we were able to measure the bioenergetic profiles of colonic adult stem and daughter cells from Lgr5-EGFP-IRES-creER(T2) transgenic mice. We examined the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a full arylhydrocarbon receptor agonist, known to affect gastrointestinal function and cancer risk, on the bioenergetic profiles of intestinal epithelial cells. Mouse colonic crypts, organoids, or sorted single cells were seeded onto Matrigel-precoated Seahorse XF24 microplates for extracellular flux analysis. Temporal analyses revealed distinct energy metabolic profiles in crypts and organoids challenged with TCDD. Furthermore, sorted Lgr5(+) stem cells exhibited a Warburg-like metabolic profile. This is noteworthy because perturbations in stem cell dynamics are generally believed to represent the earliest step toward colon tumorigenesis. We propose that our innovative methodology may facilitate future in vivo/ex vivo metabolic studies using environmental agents affecting colonocyte energy metabolism.

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Section: Tcdd Treatment Suppresses the Stem Cell Metabolic Phenotypesupporting

confidence: 82%

A bioassay to measure energy metabolism in mouse colonic crypts, organoids, and sorted stem cells

Yang

Davidson

Callaway

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The AHR [44] is more susceptible to activation by aromatic compounds than the other five receptors that we studied, and has associated toxicity. Therefore, AHR (5NJ8) was selected as the main target for the analysis of receptors.…”

Section: Analysis Of the Causes Of Decreased Bioaccumulation After Momentioning

confidence: 92%

Multiple-Site Molecular Modification of Dioxin-Like PCBs to Eliminate Bioconcentration

Li¹,

Wang²,

Chu³

et al. 2021

Pol. J. Environ. Stud.

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The environmentally friendly modification of chemical pollutants lacks the research of multiple-site simultaneous modification. In addition, there is a lack of efficient screening methods for multiple-sites of molecules, such as polychlorinated biphenyls and their derivatives. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were established using experimental bioconcentration factor (BCF) data on 58 polychlorinated biphenyls (PCBs). Based on the experimental and predicted values by 3D-QSAR, a 2 10−3 fractional factorial design with a resolution of V was used to evaluate the effects of molecular modification (single, double, or triple) at different positions on PCB bioconcentration. Finally, molecular docking technique was used to explore the mechanism of bioconcentration in the receptor of PCBs before and after multiple-site modification. The results showed that ten substitution solutions of main effect, second-order interaction effect and third-order interaction effect that significantly influenced the bioconcentration of dioxin-like PCBs were obtained. Two derivatives prepared by modification of the substituents at two sites were decoupled from the bioconcentration effect. In addition, Molecular docking results showed that the main factors affecting PCB bioconcentration were the degree of matching between hydrophilic/hydrophilic amino acid residues near the binding site and non-covalent forces formed after binding of the ligand to the receptor. The above results explore the rationality of modification schemes for low bioconcentration molecules, and provide theoretical design reference for non-bioconcentration PCBs substitutes.

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“…seen with the XRE-luc vector. As ODC1 is also a well-established target of MYC (8,9) and MYC itself has been shown to potentially be a target of AHR (50)(51)(52)(53)(54), we extended the sequence of ODC1p in the above construct to include MYC binding elements, either WT or mutated, to abrogate binding. We performed luciferase reporter assays as described above.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Bianchi‐Smiraglia¹,

Bagati²,

Fink³

et al. 2018

Journal of Clinical Investigation

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Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

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TCDD-induced activation of aryl hydrocarbon receptor regulates the skin stem cell population

Cited by 11 publications

References 29 publications

A bioassay to measure energy metabolism in mouse colonic crypts, organoids, and sorted stem cells

A bioassay to measure energy metabolism in mouse colonic crypts, organoids, and sorted stem cells

Multiple-Site Molecular Modification of Dioxin-Like PCBs to Eliminate Bioconcentration

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

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