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

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 ?-catenin, accompanied by up-regulation of I?B? (also known as NFKBIA). Furthermore, AG-205 reduced the expression of ?-TrCP (also known as BTRC), suggesting that PGRMC1 enhanced the crosstalk between NF-?B (also known as NFKB) signaling and Wnt/?-catenin signaling in an erlotinib-dependent manner. Finally, treatment with the Wnt/?-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/?-catenin and NF-?B pathways.

SUBMITTER: Lin Y 

PROVIDER: S-EPMC7076038 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature