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

• Published in: OncoTargets and therapy Vol. 8; pp. 1941 - 1948
• Main Authors: Lv, Yingqian, Zhao, Shan, Han, Jinzhu, Zheng, Likang, Yang, Zixin, Zhao, Li
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2015; Taylor & Francis Ltd; Dove Press; Dove Medical Press
• Subjects: Cell culture; chemotherapy tolerance; Colon cancer; Colorectal cancer; Drug resistance; Drug therapy; Genetic aspects; Glucose; Glycoproteins; Hypoxia; hypoxia-inducible factor-1α; Immunoglobulins; Metabolism; multidrug resistance associated protein; Multidrug resistant organisms; Original Research; Plasmids; Polymerase chain reaction; Properties; Proteins; Transcription factors; transcriptional regulation; Tumor proteins; Beijing China; United States > US; China; hypoxia; hypoxia-inducible factor-1α; multidrug resistance associated protein; chemotherapy tolerance; transcriptional regulation
• ISSN: 1178-6930; 1178-6930
• DOI: 10.2147/OTT.S82835

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.