Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells. (28th September 2020)

• Record Type: Journal Article
• Authors: Satapathy, Shakti Ranjan; Sjölander, Anita
• Is Part Of: Cancer letters. Volume 488(2020)
• Page Start: 50
• Page End: 62
• Publication Date: 2020-09-28
• Subjects: CysLT1R -- 5-FU -- Drug resistance -- Stemness -- Zebrafish -- Colon cancer; 5-FU 5-fluorouracil -- ALDH aldehyde dehydrogenase -- CC colon cancer -- CRC colorectal cancer -- CysLT1R cysteinyl leukotriene receptor 1 -- LTD4 leukotriene D4 -- Mo Montelukast -- IL-4 interleukin 4; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.05.023
• Languages: English
• ISSNs: 0304-3835

Abstract

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 CysLT1 R expression in tumors is associated with poor survival of colon cancer patients. We sought to examine the role of CysLT1 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 CysLT1 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. LTD4 /CysLT1 R signaling was further increased and abolished after CYSLTR1 CRISPR-Cas9-knockdown and reduced in CysLT1 R-doxycycline-knockdown experiments and CysLT1 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 CysLT1 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 CysLT1 R signaling by montelukast might reverse drug resistance and decrease resistance-derived stemness in colon cancer patients. Highlights: 5-FU-resistant-colon cancer (CC) cells express high levels of CysLT1 R. 5-FU-resistant-CC-cells express high levels of thymidylate synthase and active β-catenin. 5-FU-resistant-CC-cells showed increased survival and migration. The CysLT1 R antagonist montelukast reduced both 5-FU-resistant cell migration and zebrafish xenograft metastasis. Montelukast reduce 5-FU-resistant-cell-colonospheres and stemness.