Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB 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 firstline 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 upregulation 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.Lung cancer, the leading cause of cancer death worldwide, can be classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Patients diagnosed with NSCLC account for 85% of total lung cancer 1 ,

Ectodermal‐neural cortex 1 as a novel biomarker predicts poor prognosis and induces metastasis in breast cancer by promoting Wnt/β‐catenin pathway

“…Our finding that ENC1 staining is stronger in lymph metastasis tissues and knockdown of ENC1 is inhibited the β‐catenin expression supported our hypothesis. Interestingly, a putative membrane‐associated progesterone steroid receptor PGRMC1 was recently proved to be able to active β‐catenin pathway in lung adenocarcinoma 32 . And our finding ENC1 expression predicting negative expression of PR indicates the potential negative feedback between β‐catenin pathway and progesterone steroid receptor.…”

“…Interestingly, a putative membrane-associated progesterone steroid receptor PGRMC1 was recently proved to be able to active β-catenin pathway in lung adenocarcinoma. 32 And our finding ENC1 expression predicting negative expression of PR indicates the potential negative feedback between β-catenin pathway and progesterone steroid receptor. Thus, ENC1 negatively regulated the progesterone steroid receptor may through β-catenin pathway.…”

“…Interestingly, a putative membrane-associated progesterone steroid receptor PGRMC1 was recently proved to be able to active β-catenin pathway in lung adenocarcinoma. 32…”

Implications of lipid droplets in lung cancer: Associations with drug resistance (Review)

“…There are activating mutations located in the tyrosine kinase domain of the EGFR gene, including a 19-exon deletion and a point mutation in the 21 exon L858R (31)(32)(33). These activating mutations make EGFR highly sensitive to EGFR-TKIs molecular targeted drugs, such as gefitinib and erlotinib, but patients also develop resistance to these drugs (34)(35)(36). Previous studies have shown that changes in lipid metabolism in cancer cells are associated with EGFR-TKI resistance (37)(38)(39), and the inhibition of intracellular lipid droplet synthesis can reverse the resistance of cancer cells to gefitinib (40).…”

Identification of the Biomarkers and Pathological Process of Heterotopic Ossification: Weighted Gene Co-Expression Network Analysis

“…Therefore, ARF4 may play key roles in HO development. PGRMC1/Sigma-2 receptor is confirmed to play key roles in the function of tumor proliferation (such as breast tumors, lung adenocarcinoma cells, and ovarian cancer) and chemoresistance (44)(45)(46)(47). Recent research showed that PGRMC1 significantly suppresses the hydrogen peroxide-induced oxidative stress response in full-thickness fetal membrane explants and chorion cells (48).…”