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FDI-6, a FOXM1 inhibitor, activates the aryl hydrocarbon receptor and suppresses tumorsphere formation
Naoya Yamashita1, Kaho Kawai1, Minami Yoshikawa1
1Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
Abstract:
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by environmental contaminants such as dioxins and polycyclic aromatic hydrocarbons. Following ligand binding, AhR binds to xenobiotic responsive elements and modulates the transcription of AhR target genes. Multiple studies have shown that AhR plays important roles in a range of cancer cells and is attracting attention as a therapeutic target for cancer treatment. We have previously reported that AhR agonists inhibit tumorsphere formation in an AhR-dependent manner in the MCF-7 breast cancer cell line. In the present study, we found that FDI-6, an inhibitor of the transcription factor Forkhead Box M1 (FOXM1) induced the mRNA expression of AhR target genes, nuclear translocation of AhR, and transcriptional activity of AhR. In addition, FDI-6 dose-dependently reduced the mRNA expression of FOXM1-regulated genes in AhR-expressing MCF-7 cells, although not in AhR-deficient MCF-7 cells. Furthermore, FDI-6 was found to suppress tumorsphere formation via the AhR in MCF-7 cells and HepG2 human liver cancer cell line. On the basis of the findings of this study, we show that FDI-6, a FOXM1 inhibitor, functions as an AhR agonist, and suppresses tumorsphere formation via the AhR.
Insights
FDI-6, a Forkhead Box M1 (FOXM1) inhibitor, acts as an aryl hydrocarbon receptor (AhR) agonist. This compound suppresses tumorsphere formation in cancer cells by activating the AhR pathway.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- The aryl hydrocarbon receptor (AhR) is a transcription factor activated by environmental toxins, playing roles in various cancers.
- AhR is a potential therapeutic target for cancer treatment.
- AhR agonists have been shown to inhibit tumorsphere formation in breast cancer cells.
Purpose of the Study:
- To investigate the effect of FDI-6, a FOXM1 inhibitor, on AhR activity and cancer cell behavior.
- To determine if FDI-6 functions as an AhR agonist and suppresses tumorsphere formation.
Main Methods:
- Treatment of MCF-7 and HepG2 cancer cell lines with FDI-6.
- Analysis of AhR target gene expression, nuclear translocation, and transcriptional activity.
- Assessment of FOXM1-regulated gene expression in AhR-expressing and AhR-deficient cells.
- Evaluation of FDI-6's effect on tumorsphere formation.
Main Results:
- FDI-6 induced AhR target gene expression, nuclear translocation, and transcriptional activity.
- FDI-6 reduced FOXM1-regulated gene expression in an AhR-dependent manner.
- FDI-6 suppressed tumorsphere formation in both MCF-7 and HepG2 cells via AhR activation.
Conclusions:
- FDI-6, a FOXM1 inhibitor, acts as an AhR agonist.
- FDI-6 suppresses cancer cell tumorsphere formation through AhR activation.
- This study reveals a novel mechanism for FDI-6 in cancer therapy targeting the AhR pathway.
