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FoxM1 mediated resistance to gefitinib in non-small-cell lung cancer cells
1Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Aim:
Gefitinib is effective in only approximately 20% of patients with non-small-cell lung cancer (NSCLC), and the underlying mechanism remains unclear. FoxM1 is upregulated in NSCLC and associated with a poor prognosis in NSCLC patients. In this study, we examined the possible role of FoxM1 in gefitinib resistance and the related mechanisms.
Methods:
Gefitinib resistant human lung adenocarcinoma cell line SPC-A-1 and gefitinib-sensitive human lung mucoepidermoid carcinoma cell line NCI-H292 were used. mRNA and protein expression of FoxM1 and other factors were tested with quantitative RT PCR and Western blot analysis. RNA interference was performed to suppress FoxM1 expression in SPC-A-1 cells, and lentiviral infection was used to overexpress FoxM1 in H292 cells. MTT assay and flow cytometry were used to examine the proliferation and apoptosis of the cells.
Results:
Treatment of SPC-A-1 cells with gefitinib (1 and 10 μmol/L) upregulated the expression of FoxM1 in time- and concentration-dependent manners, while gefitinib (1 μmol/L) downregulated in H292 cells. In SPC-A-1 cells treated with gefitinib (1 μmol/L), the expression of several downstream targets of FoxM1, including survivin, cyclin B1, SKP2, PLK1, Aurora B kinase and CDC25B, were significantly upregulated. Overexpression of FoxM1 increased the resistance in H292 cells, while attenuated FoxM1 expression restored the sensitivity to gefitinib in SPC-A-1 cells by inhibiting proliferation and inducing apoptosis.
Conclusion:
The results suggest that FoxM1 plays an important role in the resistance of NSCLC cells to gefitinib in vitro. FoxM1 could be used as a therapeutic target to overcome the resistance to gefitinib.
Insights
Forkhead box M1 (FoxM1) promotes gefitinib resistance in non-small-cell lung cancer (NSCLC). Inhibiting FoxM1 may restore sensitivity to gefitinib in NSCLC patients, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gefitinib is effective in a limited subset of non-small-cell lung cancer (NSCLC) patients, with resistance mechanisms poorly understood.
- Forkhead box M1 (FoxM1) is frequently overexpressed in NSCLC and correlates with poor patient prognosis.
- The role of FoxM1 in mediating gefitinib resistance in NSCLC requires elucidation.
Purpose of the Study:
- To investigate the potential role of FoxM1 in the development of gefitinib resistance in NSCLC.
- To explore the underlying molecular mechanisms by which FoxM1 influences gefitinib sensitivity.
Main Methods:
- Utilized gefitinib-resistant (SPC-A-1) and -sensitive (NCI-H292) human lung cancer cell lines.
- Assessed mRNA and protein expression of FoxM1 and its downstream targets using quantitative RT-PCR and Western blotting.
- Manipulated FoxM1 levels via RNA interference (knockdown) and lentiviral overexpression.
- Evaluated cell proliferation and apoptosis using MTT assays and flow cytometry.
Main Results:
- Gefitinib treatment upregulated FoxM1 expression in resistant SPC-A-1 cells but downregulated it in sensitive NCI-H292 cells.
- FoxM1 targeted genes, including survivin, cyclin B1, SKP2, PLK1, Aurora B kinase, and CDC25B, were upregulated by gefitinib in resistant cells.
- Overexpression of FoxM1 conferred gefitinib resistance, while FoxM1 suppression restored sensitivity by inhibiting proliferation and inducing apoptosis.
Conclusions:
- FoxM1 significantly contributes to gefitinib resistance in NSCLC cells in vitro.
- FoxM1 represents a promising therapeutic target for overcoming gefitinib resistance in NSCLC.
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