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

Cancer Lett. 2020 Apr 28:476:67-74. doi: 10.1016/j.canlet.2020.02.007. Epub 2020 Feb 12.

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.

Keywords: ABC transporter; Colon cancer; Drug resistance; IRE1α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / antagonists & inhibitors*
  • 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 / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm*
  • Endoribonucleases / antagonists & inhibitors*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Female
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • Fluorouracil
  • multidrug resistance-associated protein 1