Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
In this work, a simple and sensitive electrochemiluminescence (ECL) biosensor has been devised based on target-induced steric hindrance of an antibody-modified electrode surface. Estrogen-related receptor alpha (ERRα) is closely related to estrogen-dependent tumors, which had been chosen as a model target. The ERRα antigen can bind to the antibody modified on the electrode surface with high specificity and results in the increase of steric hindrance, which prevented the ECL indicators (tris(2,2′-bipyridine) dichlororuthenium(II) hexahydrate) from approaching the electrode surface, and the ECL intensity of the system decreased. The ECL response of the system has a good linear relationship with ERRα concentration in the range of 1.0–60 ng/L, and the limit of detection is 0.5 ng/L. Different from the traditional sandwiched immune ECL detection system, which need the modification of ECL indicators on the secondary antibody, only one antibody had been used in this system. The system is easy to operate and has good sensitivity. The designed biosensor has been applied to detect ERRα in the serum and different cell line samples with satisfied results.
Septic cardiomyopathy (SCM) is a prevalent complication among septic patients, accompanied by high mortality. Estrogen‐related receptor alpha (ERRα), a transcription factor, is implicated in various cardiovascular diseases. Nonetheless, its role in SCM remains unclear. Here, the cecum ligation and puncture (CLP) procedure was used to construct a mouse sepsis model. We found that the ERRα expression was downregulated in septic hearts. Adeno-associated virus-9 (AAV-9)-mediated cardiomyocyte-specific ERRα overexpression improved the survival rate of septic mice. Additionally, ERRα overexpression ameliorated CLP-induced cardiac dysfunction and myocardial pathological damage. In vitro , HL-1 mouse cardiomyocytes were transduced with an ERRα overexpression adenovirus before LPS stimulation. The results demonstrated that ERRα overexpression mitigated LPS-induced inflammatory cytokines (IL-6, IL-1β, TNF-α, IL-18) and apoptosis (Bax, cleaved caspase-3/9) in HL-1 cells. Mechanistically, ERRα inhibited the NF-κB/NLRP3 inflammasome activation in septic hearts and LPS-stimulated HL-1 cells. Furthermore, we overlapped the differentially expressed genes of septic hearts (GSE125042) and ERRα KO hearts (GSE7196) to identify the downstream target genes. Meteorin like, glial cell differentiation regulator (METRNL) was identified as the target gene of ERRα. Notably, ERRα bound to the METRNL promoter and upregulated its activity, which was confirmed via dual-luciferase reporter assay, ChIP-qPCR, and oligonucleotide pull-down assay. Knockdown of METRNL prevented the effects of ERRα overexpression on the apoptosis and inflammatory response of cardiomyocytes induced by LPS. Our findings underscore the role of ERRα in mitigating myocardial injury in SCM, indicating its potential as a new therapeutic approach.
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