Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α

Jin Kyung Rho, Yun Jung Choi, Jin Kyung Lee, Baek Yeol Ryoo, Im II Na, Sung Hyun Yang, Cheol Hyeon Kim, Young Do Yoo, Jae Cheol Lee

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17 Citations (Scopus)

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1α protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1α expression. In our data, treatment of gefitinib suppressed induced HIF-1by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1α mRNA. The effect of gefitinib on down-regulation of HIF-1α was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1α expression. In addition, the suppression of HIF-1α using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1α by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.

Original languageEnglish
Pages (from-to)801-807
Number of pages7
JournalOncology reports
Volume21
Issue number3
DOIs
Publication statusPublished - 2009

Keywords

  • Epidermal growth factor receptor
  • Gefitinib
  • Hypoxia
  • Hypoxia-inducible factor-1α
  • Lung cancer
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Rho, J. K., Choi, Y. J., Lee, J. K., Ryoo, B. Y., Na, I. II., Yang, S. H., Kim, C. H., Yoo, Y. D., & Lee, J. C. (2009). Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1α. Oncology reports, 21(3), 801-807. https://doi.org/10.3892/or_00000287