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.

译文

在非小细胞肺癌中,表皮生长因子受体(EGFR)的突变会刺激细胞增殖和存活。 EGFR酪氨酸激酶抑制剂(EGFR-TKI)(例如埃洛替尼)被用作一线治疗,具有明显而即时的效果。然而,由于耐药性的发展,该疾病最终在大多数情况下在几年内发展。在这里,我们探讨了孕酮膜成分1(PGRMC1)在对埃洛替尼的获得性耐药中的作用,并探讨了PGRMC1诱导的EGFR-TKI耐药的分子机制。使用了对埃洛替尼敏感的细胞系PC9(源自非小细胞肺癌)和对埃洛替尼耐药的细胞系PC9 / ER。在蛋白质组学和免疫印迹分析中,PC9 / ER细胞中的PGRMC1水平高于PC9细胞中的PGRMC1水平。 WST-8分析表明,在PC9 / ER细胞中,siRNA或AG-205对PGRMC1的抑制会改变PGRMC1-血红素复合物的光谱性质,从而增加了对厄洛替尼的敏感性,而在PC9细胞中过表达PGRMC1则降低了其对ERG的敏感性。厄洛替尼。在存在厄洛替尼的情况下,免疫沉淀分析表明AG-205抑制了PC9 / ER细胞中EGFR与PGRMC1之间的相互作用。 AG-205会降低β-catenin的表达,并伴随IκBα(也称为NFKBIA)的上调。此外,AG-205降低了β-TrCP(也称为BTRC)的表达,这表明PGRMC1以依洛替尼依赖性的方式增强了NF-κB(也称为NFKB)信号传导和Wnt /β-catenin信号传导之间的串扰。最后,用Wnt /β-catenin抑制剂XAV939处理可增强PC9 / ER细胞对厄洛替尼的敏感性。这些结果表明,PGRMC1通过与PC9 / ER细胞中的EGFR结合而赋予了对厄洛替尼的抗性,从而引发Wnt /β-catenin与NF-κB通路之间的串扰。

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