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Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells

Satapathy, Shakti Ranjan LU and Sjölander, Anita LU (2020) In Cancer Letters 488. p.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.... (More)

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-derived colonospheres and in CysLT1R-Dox-knockdown cells increased colonosphere formation and stem cell markers was noticed after 5-FU treatment. IL-4-mediated stemness in both HT-29-colonospheres and 5-FU-R-cell derived colonospheres was abolished by montelukast or montelukast + 5-FU-treatment. Targeting CysLT1R signaling by montelukast might reverse drug resistance and decrease resistance-derived stemness in colon cancer patients.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5-FU, Colon cancer, CysLTR, Drug resistance, Stemness, Zebrafish
in
Cancer Letters
volume
488
pages
13 pages
publisher
Elsevier
external identifiers
  • pmid:32474153
  • scopus:85085882591
ISSN
0304-3835
DOI
10.1016/j.canlet.2020.05.023
language
English
LU publication?
yes
id
5e31211a-04ad-4042-aa9e-95dca2254612
date added to LUP
2020-06-30 07:42:58
date last changed
2024-04-17 11:12:08
@article{5e31211a-04ad-4042-aa9e-95dca2254612,
  abstract     = {{<p>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 &gt;40% resistance rate. High CysLT<sub>1</sub>R expression in tumors is associated with poor survival of colon cancer patients. We sought to examine the role of CysLT<sub>1</sub>R in 5-FU resistance and established 5-FU-resistant (5-FU-R) colon cancer cells. These 5-FU-R-cells expressed increased levels of CysLT<sub>1</sub>R 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. LTD<sub>4</sub>/CysLT<sub>1</sub>R signaling was further increased and abolished after CYSLTR1 CRISPR-Cas9-knockdown and reduced in CysLT<sub>1</sub>R-doxycycline-knockdown experiments and CysLT<sub>1</sub>R-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-derived colonospheres and in CysLT<sub>1</sub>R-Dox-knockdown cells increased colonosphere formation and stem cell markers was noticed after 5-FU treatment. IL-4-mediated stemness in both HT-29-colonospheres and 5-FU-R-cell derived colonospheres was abolished by montelukast or montelukast + 5-FU-treatment. Targeting CysLT<sub>1</sub>R signaling by montelukast might reverse drug resistance and decrease resistance-derived stemness in colon cancer patients.</p>}},
  author       = {{Satapathy, Shakti Ranjan and Sjölander, Anita}},
  issn         = {{0304-3835}},
  keywords     = {{5-FU; Colon cancer; CysLTR; Drug resistance; Stemness; Zebrafish}},
  language     = {{eng}},
  pages        = {{50--62}},
  publisher    = {{Elsevier}},
  series       = {{Cancer Letters}},
  title        = {{Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells}},
  url          = {{http://dx.doi.org/10.1016/j.canlet.2020.05.023}},
  doi          = {{10.1016/j.canlet.2020.05.023}},
  volume       = {{488}},
  year         = {{2020}},
}