The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells

O’Donnell, Edmond F.; Koch, Daniel C.; Bisson, William H.; Jang, Hyo Sang; Kolluri, Siva Kumar

doi:10.1038/cddis.2013.549

Cited by 84 publications

(83 citation statements)

References 55 publications

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“…Recent studies suggest that AhR expression is also upregulated in breast cancer (Li et al, 2014). Interestingly, the AhR ligand raloxifene was recently reported to inhibit the growth of a triple negative breast cancer cell line via an AhR-dependent mechanism (O'Donnell, et al, 2014). A similar positive therapeutic outcome was achieved with the AhR ligand omeprazole in a triple negative breast cancer cell line (Jin et al, 2014).…”

Section: Discussionmentioning

confidence: 85%

Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells

Joiakim

Mathieu

Shelp

et al. 2016

Drug Metabolism and Disposition

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CYP1A1 and CYP1A2 are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,. Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e., phosphorylated) forms of extracellular regulated kinases (ERKs) and the epidermal growth factor receptor (EGFR). Shifting to serum/EGF-deficient medium also enhanced TCDDmediated induction of cytochrome P450 (CYP)1A1. Treatment of cells cultured in complete medium with the EGFR inhibitors gefitinib (Iressa), AG1478, and CI-1033 resulted in concentration-dependent reductions of active EGFR and ERKs, and increased CYP1A1 mRNA content ∼3-to 18-fold above basal level. EGFR inhibitors synergized with TCDD and resulted in transient CYP1A1 and CYP1A2 mRNA accumulations ∼8-fold greater (maximum at 5 hours) than that achieved with only TCDD. AG1478, gefitinib, and TCDD individually induced small increases (∼1.2-to 2.5-fold) in CYP1A1 protein content but did not cause additive or synergistic accumulations of CYP1A1 protein when used in combination. The mitogen-activated protein kinase kinase inhibitor PD184352 inhibited ERK and EGFR activation in a concentration-dependent fashion without causing CYP1A1 mRNA accumulation. However, cotreatment with PD184352 potentiated TCDD-mediated CYP1A1 induction. TCDD-mediated induction of CYP1A1 in MCF7-TETon-EGFR cells, a MCF7 variant in which EGFR expression can be controlled, was not affected by the activity status of EGFR or ERKs. Hence, EGFR signaling mutes both basal and ligand-induced expression of two aryl hydrocarbon receptor-responsive P450s in MCF10A cultures. However, these effects are cell context-dependent. Furthermore, CYP1A1 mRNA and protein abundance are not closely coupled in MCF10A cultures.

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Section: Discussionmentioning

confidence: 85%

Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells

Joiakim

Mathieu

Shelp

et al. 2016

Drug Metabolism and Disposition

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“…We have previously identified Tnf and c-fos activity as the means by which aryl hydrocarbon receptor activation by the flavonoid chrysin leads to apoptosis (39). Also, the aryl hydrocarbon receptor has been found to mediate raloxifene-induced apoptosis in triple-negative breast cancer cells and estrogen receptor-deficient hepatoma cells (43). These studies represent instances in which the apoptogenic cascades activated by the AHR have been further characterized.…”

Section: Discussionmentioning

confidence: 99%

Indole-3-carbinol induces tumor cell death: function follows form

Megna

Carney

Nukaya

et al. 2016

Journal of Surgical Research

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Background Even with colonoscopy screening and preventive measures becoming more commonplace, colorectal cancer (CRC) remains the third leading cause of oncologic death in the United States as of 2014. Many chemotherapeutics exist for the treatment of colorectal cancer, though they often come with significant side effect profiles or narrow efficacy ranges in terms of patient profile. Dietary phytochemicals such as glucobrassicin and its metabolite Indole-3-carbinol (I3C) have been implicated in tumor prevention in many preclinical models across a variety of gastrointestinal tumors and represent an intriguing new class of natural chemotherapeutics for CRC. I3C has been identified as a ligand of the aryl hydrocarbon receptor (AHR), and we aimed to characterize this AHR activation in relation to its cytotoxic properties. Methods Human colorectal cancer cell lines DLD1, HCT116, HT-29, LS513, and RKO were treated with indole-3-carbinol or vehicle. Cell viability was assessed via a fluorescent product assay, and apoptotic activity was assessed via a luminescent signal tied to a ratio of caspase-3 and caspase-7 activity. Gene expression of AHR and CYP1A1 mRNA was measured using quantitative-real time-polymerase chain reaction. SiRNA stable expression lines were established on a HCT116 background using a lab-developed transfection protocol as published elsewhere. Results Multiple colorectal cancer cell types express increased CYP1A1 mRNA levels (a specific marker of AHR-driven activity) following treatment with I3C, characterizing I3C treatment as agonistic of this pathway. Also, I3C induced a dose-dependent decrease in cell viability as well as inducing apoptosis. Further, using siRNA interference to knock down AHR responsiveness generated a significant resistance to the chemotherapeutic actions of indole-3-carbinol regarding both cell viability and apoptotic activity. Conclusion Some degree of the cytotoxic and proapoptotic effects of indole-3-carbinol on colon cancer cells is dependent on activation of the aryl hydrocarbon receptor. This represents a novel mechanism for the molecular action of indole-3-carbinol and enhances our understanding of its effects in the context of colorectal cancer. Continued preclinical study of both indole-3-carbinol and the aryl hydrocarbon receptor pathway is warranted, which may one day lead to novel diet-derived colon cancer treatments that enlist the AHR.

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“…Although no binding sites were detected by bioinfor matics analyses for the aryl hydrocarbon receptor (AhR) in the promoter region of the FA2H, at least up to 10 kilobases, Δ 9 -THC has been suggested as a potential ligand for AhR due to its ability to induce the expression of CYP1A1 that is also regulated by AhR-mediated signaling in a murine hepatoma cell line (Roth et al, 2011). Based on these findings, we examined the expression levels of AhR-regulated genes, such as CYP1A2, CYP2S1, and UDP-glucuronosyltransferase 1A6 48 h after the exposure of Δ 9 -THC to MDA-MB-231 cells expressing functional AhR (Tijet et al, 2006; Beischlag et al, 2008; O’Donnell et al, 2014); however, no observable stimulation was detected, implicating the possible requirement of PPARα, but not AhR, in the induction of CYP1A1 by Δ 9 -THC in MDA-MB-231 cells. Since previous studies demonstrated that Δ 9 -THC had no binding/activation efficacy toward PPARα (Sun et al, 2006, 2007), the action point(s) of Δ 9 -THC on the induction of FA2H and CYP1A1 remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: Possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells

Takeda

Ikeda²,

et al. 2014

Toxicology

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We recently reported that Δ9-tetrahydrocannabinol (Δ9-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2 hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ9-THC treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA MB 231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ9-THC mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ9 THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ9-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ9-THC induced up regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ9 THC up-regulation of FA2H in MDA-MB-231 cells.

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The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells

Cited by 84 publications

References 55 publications

Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells

Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells

Indole-3-carbinol induces tumor cell death: function follows form

Δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: Possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells

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