論文 - 詳細
| RRC ID | 56157 |
|---|---|
| 著者 | Fujimoto M, Kito H, Kajikuri J, Ohya S. |
| タイトル | Transcriptional repression of human epidermal growth factor receptor 2 by ClC-3 Cl- /H+ transporter inhibition in human breast cancer cells. |
| ジャーナル | Cancer Sci |
| Abstract |
Recent studies have indicated that the intracellular concentration of chloride ions (Cl- ) regulates gene expression in several types of cells and that Cl- modulators positively or negatively regulate the PI3K/AKT/mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription (STAT)3 signaling pathways. We previously reported that the Ca2+ -activated Cl- channel anoctamine (ANO)1 regulated human epidermal growth factor receptor 2 (HER2) transcription in breast cancer YMB-1 cells. However, the mechanisms underlying ANO1-regulated HER2 gene expression have not yet been elucidated. In the present study, we showed the involvement of intracellular organelle ClC-3 Cl- /H+ transporter in HER2 transcription in breast cancer MDA-MB-453 cells. The siRNA-mediated inhibition of ClC-3, but not ANO1, markedly repressed HER2 transcription in MDA-MB-453 cells. Subsequently, treatments with the AKT inhibitor AZD 5363 and mTOR inhibitor everolimus significantly enhanced HER2 transcription in MDA-MB-453 cells, whereas that with the STAT3 inhibitor 5,15-diphenylporphyrin (5,15-DPP) inhibited it. AKT and mTOR inhibitors also significantly enhanced HER2 transcription in YMB-1 cells. The siRNA-mediated inhibition of ClC-3 and ANO1 resulted in increased AKT phosphorylation and decreased STAT3 phosphorylation in MDA-MB-453 and YMB-1 cells, respectively. The intracellular Cl- channel protein CLIC1 was expressed in both cells; however, its siRNA-mediated inhibition did not elicit the transcriptional repression of HER2. Collectively, our results demonstrate that intracellular Cl- regulation by ANO1/ClC-3 participates in HER2 transcription, mediating the PI3K/AKT/mTOR and/or STAT3 signaling pathway(s) in HER2-positive breast cancer cells, and support the potential of ANO1/ClC-3 blockers as therapeutic options for patients with resistance to anti-HER2 therapies. |
| 巻・号 | 109(9) |
| ページ | 2781-2791 |
| 公開日 | 2018-9-1 |
| DOI | 10.1111/cas.13715 |
| PMID | 29949674 |
| PMC | PMC6125433 |
| MeSH | Anoctamin-1 / physiology Breast Neoplasms / metabolism* Breast Neoplasms / pathology Cell Line, Tumor Chloride Channels / physiology* Chlorides / metabolism Female Gene Expression Regulation, Neoplastic* Histones / metabolism Humans Neoplasm Proteins / physiology Phosphatidylinositol 3-Kinases / physiology Proto-Oncogene Proteins c-akt / physiology Receptor, ErbB-2 / genetics* STAT3 Transcription Factor / physiology Signal Transduction / physiology TOR Serine-Threonine Kinases / physiology |
| IF | 4.751 |
| 引用数 | 4 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | MDA-MB-453(RCB1192) |