title: Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer.
abstract: 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)-1α is the key transcription factor that mediates cellular response to hypoxia. HIF-1α has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1α 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-1α 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-1α is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1α could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1α, which provides a potential novel mechanism for HIF-1α-mediated drug resistance in colon cancer and maybe other solid tumors as well.
authors.affiliation: Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Jinzhu
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Likang
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Zixin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
keywords: chemotherapy tolerance; hypoxia; hypoxia-inducible factor-1α; multidrug resistance associated protein; transcriptional regulation