PUBLICATION
Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells
- Authors
- Satapathy, S.R., Sjölander, A.
- ID
- ZDB-PUB-200601-13
- Date
- 2020
- Source
- Cancer letters 488: 50-62 (Journal)
- Registered Authors
- Keywords
- 5-FU, Colon cancer, CysLT(1)R, Drug resistance, Stemness, Zebrafish
- MeSH Terms
-
- Acetates/pharmacology
- Animals
- Antineoplastic Agents/pharmacology*
- Cell Line, Tumor
- Colonic Neoplasms/pathology*
- Cyclopropanes/pharmacology
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/physiology*
- Fluorouracil/pharmacology
- Humans
- Leukotriene Antagonists/pharmacology
- Neoplastic Stem Cells/drug effects
- Quinolines/pharmacology
- Receptors, Leukotriene/metabolism*
- Sulfides/pharmacology
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 32474153 Full text @ Cancer Lett.
Citation
Satapathy, S.R., Sjölander, A. (2020) Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells. Cancer letters. 488:50-62.
Abstract
Colon cancer is a therapy-resistant cancer with a low 5-year survival frequency. The drug 5-fluorouracil (5-FU) has been used as a first-line therapy in metastatic colon cancer in combination with leucovorin or oxaliplatin with a >40% resistance rate. High CysLT1R expression in tumors is associated with poor survival of colon cancer patients. We sought to examine the role of CysLT1R in 5-FU resistance and established 5-FU-resistant (5-FU-R) colon cancer cells. These 5-FU-R-cells expressed increased levels of CysLT1R and showed increased survival and migration compared to nonresistant cells. Increases in thymidylate synthase and active β-catenin were also observed in the 5-FU-R-cells. LTD4/CysLT1R signaling was further increased and abolished after CYSLTR1 CRISPR-Cas9-knockdown and reduced in CysLT1R-doxycycline-knockdown experiments and CysLT1R-antagonist montelukast/5-FU-treated cells. Montelukast and 5-FU resulted in synergistic effects by reducing HT-29 cell and 5-FU-R-HT-29 cell migration and zebrafish xenograft metastasis. An increase in the stem cell markers in 5-FU-R-cells and 5-FU-R-cell-derivedcolonospheres and in CysLT1R-Dox-knockdown cells increased colonosphere formation and stem cell markers after 5-FU treatment. IL-4-mediated stemness in both HT-29-colonospheres and 5-FU-R-cell-colonospheres was abolished by montelukast or montelukast + 5-FU-treated cells. Targeting CysLT1R signaling by montelukast might reverse drug resistance and decrease resistance-derived stemness in colon cancer patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping