Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells
(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.
(Less)
- author
- Satapathy, Shakti Ranjan LU and Sjölander, Anita LU
- organization
- publishing date
- 2020
- 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 >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}}, }