TR3 is involved in hypoxia-induced apoptosis resistance in lung cancer cells downstream of HIF-1α

Abstract

Objectives: Lung cancer is the leading cause of cancer death worldwide. Like in all solid tumors, hypoxia is common in lung cancer and contributes to apoptosis, and thus chemotherapy resistance. However, the underlying mechanisms are not entirely clear. TR3 (NR4A1, Nur77) is an orphan nuclear receptor that induces apoptosis and may mediate chemotherapy-induced apoptosis in cancer cells.

Materials and methods: We used A549, H23 and H1299 cell lines to investigate how TR3-mediated apoptosis is affected by hypoxia in non-small cell lung cancer (NSCLC) cells. Cell culture, western blot analysis, apoptosis assay, and siRNA-mediated gene silencing were performed in this study.

Results and conclusion: The TR3 activator cytosporone B was used to investigate TR3-mediated apoptosis in NSCLC cells under normoxic and hypoxic conditions. Cytosporone B induced apoptosis in a concentration-dependent manner. Chronic moderate hypoxia induced a significant down-regulation of TR3. Accordingly, the cytosporone B effect was reduced under these conditions. Hypoxia-induced down-regulation of TR3 was mediated by hypoxia-inducible factor 1α. Our immunoblotting analysis and expression data from a public dataset suggest that TR3 is downregulated in NSCLC. In conclusion, our findings suggest that hypoxia-induced down-regulation of TR3 might play an important role for hypoxia-induced apoptosis resistance in NSCLC.

Keywords: Apoptosis; Cytosporone B; HIF-1α; Hypoxia; Non-small cell lung cancer; TR3.