Angiogenic activities are increased via upregulation of HIF-1α expression in gefitinib-resistant non-small cell lung carcinoma cells

JEONG EUN CHA, WOOM YEE BAE, JAE SUN CHOI, SEUNG HYEUN LEE, JOO WON JEONG

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been used to treat patients with non-small cell lung cancer (NSCLC) and activating EGFR mutations; however, the emergence of secondary mutations in EGFR or the acquisition of resistance to EGFR-TKIs can develop and is involved in clinical failure. Since angiogenesis is associated with tumor progression and the blockade of antitumor drugs, inhibition of angiogenesis could be a rational strategy for developing anticancer drugs combined with EGFR-TKIs to treat patients with NSCLC. The signaling pathway mediated by hypoxia-inducible factor-1 (HIF-1) is essential for tumor angiogenesis. The present study aimed to identify the dependence of gefitinib resistance on HIF-1α activity using angiogenesis assays, western blot analysis, colony formation assay, xenograft tumor mouse model and immunohistochemical analysis of tumor tissues. In the NSCLC cell lines, HIF-1α protein expression levels and hypoxia-induced angiogenic activities were found to be increased. In a xenograft mouse tumor model, tumor tissues derived from gefitinib-resistant PC9 cells showed increased protein expression of HIF-1α and angiogenesis within the tumors. Furthermore, inhibition of HIF-1α suppressed resistance to gefitinib, whereas overexpression of HIF-1α increased resistance to gefitinib. The results from the present study provides evidence that HIF-1α was associated with the acquisition of resistance to gefitinib and suggested that inhibiting HIF-1α alleviated gefitinib resistance in NSCLC cell lines.

Original languageEnglish
Article number12932
JournalOncology Letters
Volume22
Issue number3
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Angiogenesis
  • EGFR-TKIs
  • Gefitinib
  • HIF-1α
  • NSCLC

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