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

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1 alpha expression. In our data, treatment of gefitinib suppressed induced HIF-alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1 alpha mRNA. The effect of gefitinib on down-regulation of HIF-1 alpha 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-1 alpha expression. In addition, the suppression of HIF-1 alpha 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-1 alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.