Background Platinum‐based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. Methods Platinum drug‐sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain‐of‐function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay. Results The derivative brain metastatic subpopulations (PC9‐BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM. Conclusions Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.
Glucose-regulating protein 78 (GRP78) is a molecular chaperone in the endoplasmic reticulum (ER) that promotes folding and assembly of proteins, controls the quality of proteins, and regulates ER stress signaling through Ca2+ binding to the ER. In tumors, GRP78 is often upregulated, acting as a central stress sensor that senses and adapts to changes in the tumor microenvironment, mediating ER stress of cancer cells under various stimulations of the microenvironment to trigger the folding protein response. Increasing evidence has shown that GRP78 is closely associated with the progression and poor prognosis of lung cancer, and plays an important role in the treatment of lung cancer. Herein, we reviewed for the first time the functions and mechanisms of GRP78 in the pathological processes of lung cancer, including tumorigenesis, apoptosis, autophagy, progression, and drug resistance, giving a comprehensive understanding of the function of GRP78 in lung cancer. In addition, we also discussed the potential role of GRP78 as a prognostic biomarker and therapeutic target for lung cancer, which is conducive to improving the assessment of lung cancer and the development of new therapeutic interventions.
Anti-tumor drugs can effectively shrink the lesions of primary lung cancer; however, it has limited therapeutic effect on patients with brain metastasis (BM). A BM preclinical model based on a multi-organ microfluidic chip has been established proficiently in our previous work. In this study, the BM subpopulation (PC9-Br) derived from the parental PC9 cell line was isolated from the chip model and found to develop obvious resistance to antineoplastic drugs including chemotherapeutic agents (cisplatin, carboplatin, pemetrexed) and tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR); this suggested that the acquisition of drug-resistance by brain metastatic cells was attributable to the intrinsic changes in PC9-Br. Hence, we performed proteomic and revealed a greatly altered spectrum of BM protein expression compared with primary lung cancer cells. We identified the hyperactive glutathione (GSH) metabolism pathway with the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). Aldehyde dehydrogenases (ALDH1A1, ALDH3A1) were also found to be upregulated in BM. What's more, loss of EGFR and phosphorylated EGFR in PC9-Br gave reasons for the TKIs resistance. Collectively, our findings indicated potential mechanisms for the acquirement of drug resistance occurred in BM, providing new strategies to overcome therapeutic resistance in lung cancer BM.
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