1. IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells.
- Author
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Gao Q, Li XX, Xu YM, Zhang JZ, Rong SD, Qin YQ, and Fang J
- Subjects
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B metabolism, ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Animals, Antimetabolites, Antineoplastic pharmacology, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Proliferation, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Drug Resistance, Multiple, Endoribonucleases genetics, Endoribonucleases metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Colonic Neoplasms drug therapy, Drug Resistance, Neoplasm, Endoribonucleases antagonists & inhibitors, Fluorouracil pharmacology, Multidrug Resistance-Associated Proteins antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4μ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4μ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer., Competing Interests: Declaration of competing interest The authors declare that there are no potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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