c-FLIP promotes drug resistance in non-small-cell lung cancer cells via upregulating FoxM1 expression

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Forkhead box M1 (FoxM1) is a transcription factor crucial for tumor growth and drug resistance.
• Cellular FLICE-inhibitory protein (c-FLIP) is an anti-apoptotic regulator involved in the ubiquitin-proteasome pathway.
• Both FoxM1 and c-FLIP are implicated in cancer progression and drug resistance.

Purpose of the Study:

• To investigate the effect of c-FLIP on FoxM1 expression, ubiquitination, and drug susceptibility in non-small-cell lung cancer (NSCLC).
• To explore the prognostic significance of c-FLIP and FoxM1 in NSCLC patients.
• To elucidate the mechanism by which c-FLIP influences FoxM1 and contributes to drug resistance.

Main Methods:

• Analysis of FoxM1 and c-FLIP expression levels and their correlation in 90 NSCLC patient samples.
• Prognostic analysis using survival data.
• In vitro studies using NSCLC cell lines and in vivo studies using a xenograft mouse model to assess drug resistance.
• Investigation of ubiquitination levels and regulatory pathways.

Main Results:

• FoxM1 and c-FLIP expression were positively correlated in NSCLC samples, with high levels associated with poor prognosis.
• c-FLIP stabilizes FoxM1 by inhibiting its ubiquitination, leading to increased FoxM1 expression at a post-transcriptional level.
• c-FLIP promotes resistance to thiostrepton and osimertinib in NSCLC by upregulating FoxM1, involving a feedback loop with β-catenin and p65.
• A positive feedback loop involving FoxM1, β-catenin, and p65 was identified within the c-FLIP-FoxM1 axis.

Conclusions:

• c-FLIP plays a critical role in regulating FoxM1 stability and expression in NSCLC.
• The c-FLIP-FoxM1 interaction contributes to thiostrepton and osimertinib resistance in NSCLC.
• Targeting the c-FLIP-FoxM1 axis presents a potential therapeutic strategy for NSCLC treatment.