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Metformin suppresses NFE2L1 pathway activation to inhibit gap junction beta protein expression in NSCLC
Shuo Yu1,2, Hui Ren1, Tingting Liu1
1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Objective:
Non-small-cell lung cancer (NSCLC) is a deadly form of cancer that exhibits extensive intercellular communication which contributed to chemoradiotherapy resistance. Recent evidence suggests that arrange of key proteins are involved in lung cancer progression, including gap junction proteins (GJPs).
Methods And Results:
In this study, we examined the expression patterns of GJPs in NSCLC, uncovering that both gap junction protein, beta 2 (GJB2) and gap junction protein, beta 2 (GJB3) are increased in LUAD and LUSC. We observed a correlation between the upregulation of GJB2, GJB3 in clinical samples and a worse prognosis in patients with NSCLC. By examining the mechanics, we additionally discovered that nuclear factor erythroid-2-related factor 1 (NFE2L1) had the capability to enhance the expression of connexin26 and connexin 31 in the NSCLC cell line A549. In addition, the use of metformin was discovered to cause significant downregulation of gap junction protein, betas (GJBs) by limiting the presence of NFE2L1 in the cytoplasm.
Conclusion:
This emphasizes the potential of targeting GJBs as a viable treatment approach for NSCLC patients receiving metformin.
Insights
Gap junction proteins (GJPs) like GJB2 and GJB3 are upregulated in non-small-cell lung cancer (NSCLC), correlating with poor prognosis. Metformin downregulates GJPs by affecting NFE2L1, suggesting a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small-cell lung cancer (NSCLC) is characterized by intercellular communication, contributing to treatment resistance.
- Gap junction proteins (GJPs) are implicated in lung cancer progression.
Purpose of the Study:
- To investigate the expression patterns of GJPs in NSCLC.
- To explore the regulatory mechanisms of GJP expression and the effect of metformin on GJPs in NSCLC.
Main Methods:
- Analysis of GJP expression in NSCLC clinical samples.
- Examination of NFE2L1's role in regulating connexin expression in NSCLC cell lines (A549).
- Assessment of metformin's effect on GJP expression and NFE2L1 localization.
Main Results:
- Both GJB2 and GJB3 were found to be upregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
- Increased GJB2 and GJB3 expression correlated with a worse prognosis in NSCLC patients.
- NFE2L1 enhances connexin26 and connexin31 expression in NSCLC cells.
- Metformin significantly downregulates GJPs by reducing cytoplasmic NFE2L1.
Conclusions:
- Targeting GJPs represents a potential therapeutic strategy for NSCLC patients, particularly when combined with metformin treatment.
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