Metabolic targeting of HIF-1α potentiates the therapeutic efficacy of oxaliplatin in colorectal cancer
Journal
Oncogene
Journal Volume
39
Journal Issue
2
Pages
414-427
Date Issued
2020
Author(s)
Abstract
Drug resistance is a major problem limiting the efficacy of chemotherapy in cancer treatment, and the hypoxia-induced stabilization of HIF-1α plays a role in this process. HIF-1α overexpression has been observed in a variety of human cancers, including colorectal cancer (CRC). Therefore, targeting HIF-1α is a promising strategy for overcoming chemoresistance to enhance the efficacy of chemotherapies in CRC. Here, we show that DNMT inhibitors can induce HIF-1α degradation to overcome oxaliplatin resistance and enhance anti-CRC therapy. We found that a low-toxicity DNMT inhibitor, zebularine, could downregulate HIF-1α expression and overcome hypoxia-induced oxaliplatin resistance in HCT116 cells and showed efficacy in HCT116 xenograft models and AOM/DSS-induced CRC mouse models. Zebularine could induce the degradation of HIF-1α protein through hydroxylation. LC-MS analysis showed a decrease in succinate in various CRC cells under hypoxia and in colon tissues of AOM/DSS-induced CRC mice. The decrease was reversed by zebularine. Tumor angiogenesis was also reduced by zebularine. Furthermore, zebularine potentiated the anticancer effect of oxaliplatin in AOM/DSS-induced CRC models. This finding provides a new strategy in which an increase in HIF-1α hydroxylation could overcome oxaliplatin resistance to enhance anti-CRC therapy. ? 2019, The Author(s), under exclusive licence to Springer Nature Limited.
SDGs
Other Subjects
azoxymethane; dextran sulfate; DNA methyltransferase inhibitor; hypoxia inducible factor 1alpha; oxaliplatin; succinic acid; zebularine; antineoplastic agent; cytidine; HIF1A protein, human; hypoxia inducible factor 1alpha; oxaliplatin; pyrimidin-2-one beta-ribofuranoside; vasculotropin A; angiogenesis; animal cell; animal experiment; animal model; animal tissue; antiangiogenic activity; antineoplastic activity; Article; cancer inhibition; colon tissue; colorectal cancer; controlled study; down regulation; drug efficacy; drug hydroxylation; drug potentiation; drug structure; drug targeting; female; HCT 116 cell line; human; human cell; hypoxia; liquid chromatography-mass spectrometry; monotherapy; mouse; nonhuman; priority journal; protein degradation; protein expression; protein synthesis inhibition; structure analysis; tumor xenograft; animal; colorectal tumor; drug effect; drug potentiation; drug resistance; drug screening; gene expression regulation; hydroxylation; metabolism; molecularly targeted therapy; neovascularization (pathology); pathology; protein stability; vascularization; Animals; Antineoplastic Agents; Colorectal Neoplasms; Cytidine; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hydroxylation; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Molecular Targeted Therapy; Neovascularization, Pathologic; Oxaliplatin; Protein Stability; Proteolysis; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays
Type
journal article