IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells.

Autor: Gao Q; Shanghai Institute of Nutrition and Health, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China., Li XX; Shanghai Institute of Nutrition and Health, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China., Xu YM; Shanghai Institute of Nutrition and Health, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China., Zhang JZ; Shanghai Institute of Nutrition and Health, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China., Rong SD; Shanghai Institute of Nutrition and Health, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China., Qin YQ; Shanghai Institute of Nutrition and Health, Shanghai Institutes of Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China., Fang J; Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, 266061, China; Cancer Institute, Qingdao University, Qingdao, 266061, China. Electronic address: jfang2018@163.com.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2020 Apr 28; Vol. 476, pp. 67-74. Date of Electronic Publication: 2020 Feb 12.
DOI: 10.1016/j.canlet.2020.02.007
Abstrakt: 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.)
Databáze: MEDLINE
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