論文

査読有り 国際誌
2020年3月16日

Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells.

Scientific reports
  • Ying Lin
  • ,
  • Kazuma Higashisaka
  • ,
  • Takuya Shintani
  • ,
  • Ayaka Maki
  • ,
  • Sachiyo Hanamuro
  • ,
  • Yuya Haga
  • ,
  • Shinichiro Maeda
  • ,
  • Hirofumi Tsujino
  • ,
  • Kazuya Nagano
  • ,
  • Yasushi Fujio
  • ,
  • Yasuo Tsutsumi

10
1
開始ページ
4748
終了ページ
4748
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41598-020-61727-3

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.

リンク情報
DOI
https://doi.org/10.1038/s41598-020-61727-3
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32179851
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076038
ID情報
  • DOI : 10.1038/s41598-020-61727-3
  • PubMed ID : 32179851
  • PubMed Central 記事ID : PMC7076038

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