Characterization of Glyceollins as Novel Aryl Hydrocarbon Receptor Ligands and Their Role in Cell Migration

Pham, Thu Ha; Lecomte, Sylvain; Guével, Rémy Le; Lardenois, Aurélie; Evrard, Bertrand; Chalmel, Frédéric; Ferrière, François; Balaguer, Patrick; Efstathiou, Théo; Pakdel, Farzad

doi:10.3390/ijms21041368

Cited by 12 publications

(6 citation statements)

References 57 publications

(89 reference statements)

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“…The reporter HAhLH cell line was obtained by transfecting human HeLa cells with the dioxin-responsive gene XRE(TnGCGTG) 3 -tata-luciferase-Luc-hygromycin plasmid as described before 43 . H4AhLH and ZAhLH cell lines were obtained in a similar way by transfecting rat H4IIE and zebrafish ZFL cells with the dioxin-responsive gene XRE(TnGCGTG) 3 -tata-luciferase-Luc-hygromycin plasmid.…”

Section: Methodsmentioning

confidence: 99%

Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex

et al. 2022

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The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including pollutants, natural products and metabolites. However, the scarcity of structural data precludes understanding of how AHR is activated by such diverse compounds. Our 2.85 Å structure of the human indirubin-bound AHR complex with the chaperone Hsp90 and the co-chaperone XAP2, reported herein, reveals a closed conformation Hsp90 dimer with AHR threaded through its lumen and XAP2 serving as a brace. Importantly, we disclose the long-awaited structure of the AHR PAS-B domain revealing a unique organisation of the ligand-binding pocket and the structural determinants of ligand-binding specificity and promiscuity of the receptor. By providing structural details of the molecular initiating event leading to AHR activation, our study rationalises almost forty years of biochemical data and provides a framework for future mechanistic studies and structure-guided drug design.

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Section: Methodsmentioning

confidence: 99%

Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex

et al. 2022

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“…It has been reported that TCDD, BAP, pyocyanin, indoxyl sulfate, and other agonists can induce the migration and invasion of human breast cancer MDA-MB-231, Hs578T, SUM149 cells, oral squamous cell carcinoma via activating the AhR signaling pathway ( Stanford et al, 2016 ; Narasimhan et al, 2018 ; Shadboorestan et al, 2019 ). While agonists 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), omeprazole, glyceolin I, glyceolin II can target AhR to limit the expression of migration regulatory factors MYH9, CXCL12, CXCR4, MMP9, CDH2, CCL2 and inhibit the migration and proliferation of glioblastoma or human breast cancer cells ( Hall et al, 2010 ; Pham et al, 2020 ; Zhao L. et al, 2020 ). Notably, the influences of AhR on tumors are tissue or ligand-specific.…”

Section: Discussionmentioning

confidence: 99%

Rutaecarpine Inhibits U87 Glioblastoma Cell Migration by Activating the Aryl Hydrocarbon Receptor Signaling Pathway

Liu

Chen

Zhu

et al. 2021

Front. Mol. Neurosci.

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Glioblastoma is the most frequent and aggressive primary astrocytoma in adults. The high migration ability of the tumor cells is an important reason for the high recurrence rate and poor prognosis of glioblastoma. Recently, emerging evidence has shown that the migration ability of glioblastoma cells was inhibited upon the activation of aryl hydrocarbon receptor (AhR), suggesting potential anti-tumor effects of AhR agonists. Rutaecarpine is a natural compound with potential tumor therapeutic effects which can possibly bind to AhR. However, its effect on the migration of glioblastoma is unclear. Therefore, we aim to explore the effects of rutaecarpine on the migration of human glioblastoma cells U87 and the involvement of the AhR signaling pathway. The results showed that: (i) compared with other structural related alkaloids, like evodiamine and dehydroevodiamine, rutaecarpine was a more potent AhR activator, and has a stronger inhibitory effect on the glioblastoma cell migration; (ii) rutaecarpine decreased the migration ability of U87 cells in an AhR-dependent manner; (iii) AhR mediated the expression of a tumor suppressor interleukin 24 (IL24) induced by rutaecarpine, and AhR-IL24 axis was involved in the anti-migratory effects of rutaecarpine on the glioblastoma. Besides IL24, other candidates AhR downstream genes both associated with cancer and migration were proposed to participate in the migration regulation of rutaecarpine by RNA-Seq and bioinformatic analysis. These data indicate that rutaecarpine is a naturally-derived AhR agonist that could inhibit the migration of U87 human glioblastoma cells mostly via the AhR-IL24 axis.

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“…3,4,5-Trihydroxy-6-methylphthaldehyde (Flavipin) is a fungal metabolite that inhibits T47D, and MDA-MB-231 cell growth, invasion and migration and these responses are blunted after AhR knockdown [ 131 ]. Glyceollins ( Figure 3 ) are soybean phytoalexins that are AhR ligands and both glyceollin I and glyceollin II inhibit migration of MDA-MB-231 cells [ 132 ]. Camalexin, an indole phytoalexin, 2-hydroxy-6-tridecylbenzoic acid and the polyphenolic gallic acid, are also phytochemical AhR ligands that exhibit anticancer activity in breast cancer [ 133 , 134 ].…”

Section: Role Of the Ahr And Its Ligands As Inhibitors Breast Cancer ...mentioning

confidence: 99%

The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer

Safe

Zhang

2022

Cancers

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Breast cancer is a complex disease which is defined by numerous cellular and molecular markers that can be used to develop more targeted and successful therapies. The aryl hydrocarbon receptor (AhR) is overexpressed in many breast tumor sub-types, including estrogen receptor -positive (ER+) tumors; however, the prognostic value of the AhR for breast cancer patient survival is not consistent between studies. Moreover, the functional role of the AhR in various breast cancer cell lines is also variable and exhibits both tumor promoter- and tumor suppressor- like activity and the AhR is expressed in both ER-positive and ER-negative cells/tumors. There is strong evidence demonstrating inhibitory AhR-Rα crosstalk where various AhR ligands induce ER degradation. It has also been reported that different structural classes of AhR ligands, including halogenated aromatics, polynuclear aromatics, synthetic drugs and other pharmaceuticals, health promoting phytochemical-derived natural products and endogenous AhR-active compounds inhibit one or more of breast cancer cell proliferation, survival, migration/invasion, and metastasis. AhR–dependent mechanisms for the inhibition of breast cancer by AhR agonists are variable and include the downregulation of multiple genes/gene products such as CXCR4, MMPs, CXCL12, SOX4 and the modulation of microRNA levels. Some AhR ligands, such as aminoflavone, have been investigated in clinical trials for their anticancer activity against breast cancer. In contrast, several publications have reported that AhR agonists and antagonists enhance and inhibit mammary carcinogenesis, respectively, and differences between the anticancer activities of AhR agonists in breast cancer may be due in part to cell context and ligand structure. However, there are reports showing that the same AhR ligand in the same breast cancer cell line gives opposite results. These differences need to be resolved in order to further develop and take advantage of promising agents that inhibit mammary carcinogenesis by targeting the AhR.

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Characterization of Glyceollins as Novel Aryl Hydrocarbon Receptor Ligands and Their Role in Cell Migration

Cited by 12 publications

References 57 publications

Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex

Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex

Rutaecarpine Inhibits U87 Glioblastoma Cell Migration by Activating the Aryl Hydrocarbon Receptor Signaling Pathway

The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer

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