Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer

Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1 alpha is the key transcription factor that mediates cellular response to hypoxia. HIF-1 alpha has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1 alpha and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1) were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1 alpha by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1 alpha is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1 alpha could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1 alpha, which provides a potential novel mechanism for HIF-1 alpha-mediated drug resistance in colon cancer and maybe other solid tumors as well.