FoxM1 mediated resistance to gefitinib in non-smallcell lung cancer cells

Nuo Xu, Xin Zhang, Xun Wang, Hai Yan Ge, Xiao Ying Wang, David Garfield, Ping Yang, Yuan Lin Song, Chun Xue Bai

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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 10mol/L) upregulated the expression of FoxM1 in time-and concentration-dependent manners, while gefitinib (1mol/L) downregulated in H292 cells. In SPC-A-1 cells treated with gefitinib (1mol/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.

Original languageEnglish (US)
Pages (from-to)675-681
Number of pages7
JournalActa Pharmacologica Sinica
Volume33
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • Drug resistance
  • FoxM1
  • Gefitinib
  • Human lung adenocarcinoma cell
  • Human lung mucoepidermoid carcinoma cell
  • Non-small-cell lung cancer
  • RNA interference

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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