RRC ID 58810
Author Lin Y, Higashisaka K, Shintani T, Maki A, Hanamuro S, Haga Y, Maeda S, Tsujino H, Nagano K, Fujio Y, Tsutsumi Y.
Title Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells.
Journal 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.
Volume 10(1)
Pages 4748
Published 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
Human and Animal Cells PC-9(RCB4455)