Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell

The International Journal of Biochemistry & Cell Biology
Jiuda ZhaoBinghe Xu

Abstract

EPAS-1/HIF-2α (Endothelial PAS domain-containing protein 1/hypoxia-inducible transcription factors 2α) is a transcription factor expressed in a wide range of human cancers, including stomach cancer. Although EPAS-1 has been studied for years, its function in oncogenic transformation processes needs to be further investigated. In this study, we found that EPAS-1 would promote the growth of stomach cancer cell line BGC-823. Our results revealed that EPAS-1 interacts with Pregnane X Receptor (PXR), a nuclear receptor that regulates multiple genes' transcription involved in multi-drugs resistance (MDR) process. Protein-protein interaction between EPAS-1 and PXR was identified by co-immunoprecipitation and GST-pull down assays. By this interaction, EPAS-1 recruited PXR to its response elements in promoter/enhancer regions of CYP3A4, a PXR target gene. Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel. Reduction of EPAS-1 level via its siRNA disrupted the proliferation, and enhanced the susceptibility of BGC-823 cells to those chemotherape...Continue Reading

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