論文 - 詳細
| RRC ID | 58810 |
|---|---|
| 著者 | Lin Y, Higashisaka K, Shintani T, Maki A, Hanamuro S, Haga Y, Maeda S, Tsujino H, Nagano K, Fujio Y, Tsutsumi Y. |
| タイトル | Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells. |
| ジャーナル | Sci Rep |
| Abstract |
In non-small-cell lung cancer, mutation of epidermal growth factor receptor (EGFR) stimulates cell proliferation and survival. EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib are used as first-line therapy with drastic and immediate effectiveness. However, the disease eventually progresses in most cases within a few years due to the development of drug resistance. Here, we explored the role of progesterone membrane component 1 (PGRMC1) in acquired resistance to erlotinib and addressed the molecular mechanism of EGFR-TKI resistance induced by PGRMC1. The erlotinib-sensitive cell line PC9 (derived from non-small-cell lung cancer) and the erlotinib-resistant cell line PC9/ER were used. In proteomic and immunoblotting analyses, the PGRMC1 level was higher in PC9/ER cells than in PC9 cells. WST-8 assay revealed that inhibition of PGRMC1 by siRNA or AG-205, which alters the spectroscopic properties of the PGRMC1-heme complex, in PC9/ER cells increased the sensitivity to erlotinib, and overexpression of PGRMC1 in PC9 cells reduced their susceptibility to erlotinib. In the presence of erlotinib, immunoprecipitation assay showed that AG-205 suppressed the interaction between EGFR and PGRMC1 in PC9/ER cells. AG-205 decreased the expression of β-catenin, accompanied by up-regulation of IκBα (also known as NFKBIA). Furthermore, AG-205 reduced the expression of β-TrCP (also known as BTRC), suggesting that PGRMC1 enhanced the crosstalk between NF-κB (also known as NFKB) signaling and Wnt/β-catenin signaling in an erlotinib-dependent manner. Finally, treatment with the Wnt/β-catenin inhibitor XAV939 enhanced the sensitivity of PC9/ER cells to erlotinib. These results suggest that PGRMC1 conferred resistance to erlotinib through binding with EGFR in PC9/ER cells, initiating crosstalk between the Wnt/β-catenin and NF-κB pathways. |
| 巻・号 | 10(1) |
| ページ | 4748 |
| 公開日 | 2020-3-16 |
| DOI | 10.1038/s41598-020-61727-3 |
| PII | 10.1038/s41598-020-61727-3 |
| PMID | 32179851 |
| PMC | PMC7076038 |
| MeSH | Adenocarcinoma / genetics* Adenocarcinoma / metabolism Adenocarcinoma / pathology* Antineoplastic Agents* Cell Line, Tumor Drug Resistance, Neoplasm / genetics* ErbB Receptors / metabolism Erlotinib Hydrochloride / pharmacology* Humans Lung Neoplasms / genetics* Lung Neoplasms / metabolism Lung Neoplasms / pathology* Membrane Proteins / metabolism* NF-kappa B / metabolism* Protein Kinase Inhibitors* Receptors, Progesterone / metabolism* Signal Transduction / genetics* Wnt Proteins / metabolism* Wnt Signaling Pathway / genetics* beta Catenin / metabolism* |
| IF | 3.998 |
| 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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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |