Activation of aryl hydrocarbon receptor signaling by gallic acid suppresses progression of human breast cancer in vitro and in vivo

Hanieh, Hamza; Ibrahim, Hairul-Islam Mohamed; Maged, Mohammed; Alwassil, Osama I.; Abukhalil, Mohammad H.; Farhan, Mahdi

doi:10.1016/j.phymed.2021.153817

Cited by 10 publications

(15 citation statements)

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Section: Role Of (Poly)phenols and Derived Metabolites In The Ahr Mod...mentioning

confidence: 99%

“…3,4,5-trihydroxybenzoic acid (gallic acid), a gut metabolite, but also a parent compound present in some fruits (i.e., berries), is one of the most studied metabolites as an AHR modulator [ 234 , 235 , 251 , 252 ]. In silico analysis pointed out gallic acid as a ligand of the AHR [ 251 , 252 ]. In vitro tests in different cell types (breast cancer cells, T cells, macrophages) indicate that gallic acid is an agonist of the AHR, capable of inducing AHR nuclear translocation and expression of AHR target genes, such as Cyp1a1 [ 251 , 252 ].…”

Section: Role Of (Poly)phenols and Derived Metabolites In The Ahr Mod...mentioning

confidence: 99%

“…In silico analysis pointed out gallic acid as a ligand of the AHR [ 251 , 252 ]. In vitro tests in different cell types (breast cancer cells, T cells, macrophages) indicate that gallic acid is an agonist of the AHR, capable of inducing AHR nuclear translocation and expression of AHR target genes, such as Cyp1a1 [ 251 , 252 ]. In an in vitro breast cancer model, gallic acid promoted apoptosis of the cancer cells and decreased proliferation, migration and invasion capacities in an AHR dependent manner [ 251 ].…”

Section: Role Of (Poly)phenols and Derived Metabolites In The Ahr Mod...mentioning

confidence: 99%

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Targeting the aryl hydrocarbon receptor by gut phenolic metabolites: A strategy towards gut inflammation

et al. 2023

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Section: Role Of (Poly)phenols and Derived Metabolites In The Ahr Mod...mentioning

confidence: 99%

Section: Role Of (Poly)phenols and Derived Metabolites In The Ahr Mod...mentioning

confidence: 99%

Section: Role Of (Poly)phenols and Derived Metabolites In The Ahr Mod...mentioning

confidence: 99%

See 1 more Smart Citation

Targeting the aryl hydrocarbon receptor by gut phenolic metabolites: A strategy towards gut inflammation

et al. 2023

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“…After 4 h of cell incubation for recovery, the nucleofector medium (serumfree DMEM with 1% glutamine) was changed to a 10% serum DMEM containing DMSO or OT 25 µM. The transfected cells were further analyzed for cell proliferation, migration, invasion and COX-2 expression using real-time PCR and Western blot techniques [72].…”

Section: Cell Transfection Of Short Interference Cox-2 In A549 Cancer Cell Linesmentioning

confidence: 99%

Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a

et al. 2022

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Cancer is a severe health condition and considered one of the major healthcare issues and is in need of innovative strategy for a cure. The current study aimed to investigate the chemical profile of Trigonella hamosa L. and a potential molecular approach to explain its regulation in cancer progression through an inflammatory mediator (COX-2) in A549 non-small lung cancer cell lines via in silico, mechanistic and molecular aspects. T. hamosa was extracted and then subjected to a CCK-8 cell viability assay in different cancer cell lines including MDA-MB-231, A549 and HCT-116. Total extract was subjected to several chromatographic techniques to yield orientin (OT); the structure was elucidated by inspection of NMR spectroscopic data. To achieve anticancer effects of OT, a cell viability assay using a CCK-8 kit, immunoprecipitation by Western blot, cell migration using a wound healing assay, cell invasion using a Matrigel-Transwell assay, apoptosis by AO/EB dual staining, flow cytometric analysis and DAPI staining, a silenced COX-2 model to determine PGE-2 production and real-time PCR and Western blot of BCL-2, CYP-1A1, iNOS and COX-2 markers were carried out. The results demonstrated that OT decreased the cell proliferation and controlled cell migration and invasive properties. OT destabilized the COX-2 mRNA and downregulated its expression in A549 cell lines. Virtual binding showed interaction (binding energy −10.43) between OT and COX-2 protein compared to the selective COX-2 inhibitor celecoxib (CLX) (binding energy −9.4). The OT-CLX combination showed a superior anticancer effect. The synergistic effect of OT-CLX combination was noticed in controlling the migration and invasion of A549 cell lines. OT-CLX downregulated the expression of BCL-2, iNOS and COX-2 and activated the proapoptotic gene CYP-1A1. OT mitigated the COX-2 expression via upregulation of miR-26b and miR-146a. Interestingly, COX-2-silenced transfected A549 cells exhibited reduced expression of miR-26b and miR-146a. The findings confirmed the direct interaction of OT with COX-2 protein. PGE-2 expression was quantified in both naïve and COX-2-silenced A549 cells. OT downregulated the release of PGE-2 in both tested conditions. These results confirmed the regulatory effect of OT on A549 cell growth in a COX-2-dependent manner. OT activated apoptosis via activation of CYP-1A1 expression in an independent manner. These results revealed that the OT-CLX combination could serve as a potential synergistic treatment for effective inflammatory-mediated anticancer strategies.

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“…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 ]. Gallic acid inhibits tumor growth in athymic mouse xenograft models bearing MDA-MB-231 and T47D cells, and also inhibited growth, migration, and invasion in cell culture [ 135 ].…”

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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Activation of aryl hydrocarbon receptor signaling by gallic acid suppresses progression of human breast cancer in vitro and in vivo

Cited by 10 publications

References 44 publications

Targeting the aryl hydrocarbon receptor by gut phenolic metabolites: A strategy towards gut inflammation

Targeting the aryl hydrocarbon receptor by gut phenolic metabolites: A strategy towards gut inflammation

Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a

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

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