| 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
|
| Resource |
| Human and Animal Cells |
PC-9(RCB4455) |
