The Inhibitory Mechanisms of the Tyrosine Kinase Inhibitors Herbimycin A, Genistein, and Tyrphostin B48 with Regard to the Function of the Aryl Hydrocarbon Receptor in Caco-2 Cells

Kasai, Shuya; Kikuchi, Hideaki

doi:10.1271/bbb.90438

Cited by 15 publications

(8 citation statements)

References 33 publications

(35 reference statements)

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“…Consistent with our work with UACC3199 cells [42], the increase in BRCA1 protein observed with GEN treatment in HCC38 cells was associated on average with an ~30% decrease ( p = 0.05) in CpG methylation at the BRCA1 promoter (Figure 4A). As a control, we determined that the stimulatory effects of GAL on BRCA1 protein levels were also associated a with a decrease (~25%) in BRCA1 promoter methylation (Figure 4B, p = 0.02), based on the information that GEN is an antagonist of AHR transcriptional activity in colon cancer cells [50] and a dual agonist/antagonist in ER + BC cells [51].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Activation of BRCA1 by Genistein In Vivo and Triple Negative Breast Cancer Cells Linked to Antagonism toward Aryl Hydrocarbon Receptor

et al. 2019

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Triple negative breast cancers (TNBC) are the most aggressive and lethal breast cancers (BC). The aryl hydrocarbon receptor (AHR) is often overexpressed in TNBC, and its activation results in the epigenetic silencing of BRCA1, which is a necessary factor for the transcriptional activation of estrogen receptor (ER)α. The dietary isoflavone genistein (GEN) modulates BRCA1 CpG methylation in BC cells. The purpose of this study was to investigate the effect of GEN on BRCA1 epigenetic regulation and AHR activity in vivo and TNBC cells. Mice were administered a control or GEN-enriched (4 and 10 ppm) diet from gestation through post-natal day 50. Mammary tissue was analyzed for changes in BRCA1 regulation and AhR activity. TNBC cells with constitutively hypermethylated BRCA1 (HCC38) and MCF7 cells were used. Protein levels and mRNA expression were measured by Western blot and real-time PCR, respectively. BRCA1 promoter occupancy and CpG methylation were analyzed by chromatin immunoprecipitation and methylation-specific PCR, respectively. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. GEN administered in the diet dose-dependently decreased basal Brca1 methylation and AHR activity in the mammary gland of adult mice. HCC38 cells were found to overexpress constitutively active AHR in parallel with BRCA1 hypermethylation. The treatment of HCC38 cells with GEN upregulated BRCA1 protein levels, which was attributable to decreased CpG methylation and AHR binding at BRCA1 exon 1a. In MCF7 cells, GEN prevented the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-dependent localization of AHR at the BRCA1 gene. These effects were consistent with those elicited by control AHR antagonists galangin (GAL), CH-223191, and α-naphthoflavone. The pre-treatment with GEN sensitized HCC38 cells to the antiproliferative effects of 4-hydroxytamoxifen. We conclude that the dietary compound GEN may be effective for the prevention and reversal of AHR-dependent BRCA1 hypermethylation, and the restoration of ERα-mediated response, thus imparting the sensitivity of TNBC to antiestrogen therapy.

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Section: Resultsmentioning

confidence: 99%

Epigenetic Activation of BRCA1 by Genistein In Vivo and Triple Negative Breast Cancer Cells Linked to Antagonism toward Aryl Hydrocarbon Receptor

et al. 2019

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“…Here, we confirmed that IS, like IAA, does not induce AHR binding to F3 promoter after endothelial stimulation, supporting that TF upregulation via IS/AHR is mediated by a non-genomic pathway. Interestingly, we found that genistein, which inhibits AHR nuclear translocation [18] and the upregulation of genes from the AHR genomic pathway, does not inhibit TF mRNA upregulation mediated by IS. This is consistent with an upregulation of TF independent of AHR genomic pathway.…”

Section: Discussionmentioning

confidence: 75%

“…Using experiments of AHR inhibition, we demonstrated that both shear stress and IS upregulate COX2, as well as CYP1A1 and CYP1B1 mRNA expression, in an AHR-dependent way. We examined the effect of genistein treatment, which was shown to inhibit AHR nuclear translocation [18]. Genistein activities as an AHR agonist and antagonist depend on cell context [21].…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed the effect of genistein, an inhibitor of tyrosine kinases that also inhibits AHR nuclear translocation [18]. Genistein strongly inhibited the induction by shear stress of all AHR target genes: AHRR ( Figure 4A), PTGS2 (COX2) ( Figure 4B), CYP1A1 ( Figure 4C), and CYP1B1 ( Figure 4D).…”

Section: Genistein Suppressed Shear Stress-and Is-mediated Ahr Targetmentioning

confidence: 99%

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Aryl Hydrocarbon Receptor Activation and Tissue Factor Induction by Fluid Shear Stress and Indoxyl Sulfate in Endothelial Cells

Lano

Laforet

Kotze

et al. 2020

IJMS

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Endogenous agonists of the transcription factor aryl hydrocarbon receptor (AHR) such as the indolic uremic toxin, indoxyl sulfate (IS), accumulate in patients with chronic kidney disease. AHR activation by indolic toxins has prothrombotic effects on the endothelium, especially via tissue factor (TF) induction. In contrast, physiological AHR activation by laminar shear stress (SS) is atheroprotective. We studied the activation of AHR and the regulation of TF by IS in cultured human umbilical vein endothelial cells subjected to laminar fluid SS (5 dynes/cm2). SS and IS markedly increased the expression of AHR target genes PTGS2 (encoding for COX2), AHRR, CYP1A1, and CYP1B1, as well as F3 (encoding for TF), in an AHR-dependent way. IS amplified SS-induced TF mRNA and protein expression and upregulation of AHR target genes. Interestingly, tyrosine kinase inhibition by genistein decreased SS- but not IS-induced TF expression. Finally, the increase in TF expression induced by laminar SS was not associated with increased TF activity. In contrast, IS increased TF activity, even under antithrombotic SS conditions. In conclusion, IS and SS induce AHR activation and AHR-dependent TF upregulation by different mechanisms. Impairment of the antithrombotic properties of shear stressed endothelium by toxic AHR agonists could favor cardiovascular diseases in CKD.

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“…The authors suggested that the decrease in AhR protein resulted in anticancer properties of soy products containing genistein and other phytoestrogens. Other studies performed in various cell lines indicated that genistein might act as an AhR agonist or antagonist, and potentiate or diminish the effect of typical AhR ligands such as TCDD [ 14 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

The combined effects of 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin and the phytoestrogen genistein on steroid hormone secretion, AhR and ERβ expression and the incidence of apoptosis in granulosa cells of medium porcine follicles

Piasecka-Srader

Sadowska

Nynca

et al. 2016

Journal of Reproduction and Development

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Low doses of endocrine disrupting chemicals (EDCs) used in combination may act in a manner different from that of individual compounds. The objective of the study was to examine in vitro effects of low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 100 pM) and genistein (500 nM) on: 1) progesterone (P4) and estradiol (E2) secretion (48 h); 2) dynamic changes in aryl hydrocarbon receptor (AhR) mRNA and protein expression (1, 3, 6, 24 and 48 h); 3) dynamic changes in estrogen receptor β (ERβ) mRNA and protein expression (1, 3, 6, 24 and 48 h); and 4) induction of apoptosis in porcine granulosa cells derived from medium follicles (3, 6 and 24 h). TCDD had no effect on P4 or E2 production, but potentiated the inhibitory effect of genistein on P4 production. In contrast to the individual treatments which did not produce any effects, TCDD and genistein administered together decreased ERβ and AhR protein expression in granulosa cells. Moreover, the inhibitory effect of TCDD on AhR mRNA expression was abolished by genistein. The treatments did not induce apoptosis in the cells. In summary, combined effects of low concentrations of TCDD and genistein on follicular function of pigs differed from that of individual compounds. The results presented in the current paper clearly indicate that effects exerted by low doses of EDCs applied in combination must be taken into consideration when studying potential risk effects of EDCs on biological processes.

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The Inhibitory Mechanisms of the Tyrosine Kinase Inhibitors Herbimycin A, Genistein, and Tyrphostin B48 with Regard to the Function of the Aryl Hydrocarbon Receptor in Caco-2 Cells

Cited by 15 publications

References 33 publications

Epigenetic Activation of BRCA1 by Genistein In Vivo and Triple Negative Breast Cancer Cells Linked to Antagonism toward Aryl Hydrocarbon Receptor

Epigenetic Activation of BRCA1 by Genistein In Vivo and Triple Negative Breast Cancer Cells Linked to Antagonism toward Aryl Hydrocarbon Receptor

Aryl Hydrocarbon Receptor Activation and Tissue Factor Induction by Fluid Shear Stress and Indoxyl Sulfate in Endothelial Cells

The combined effects of 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin and the phytoestrogen genistein on steroid hormone secretion, AhR and ERβ expression and the incidence of apoptosis in granulosa cells of medium porcine follicles

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