例如:"lncRNA", "apoptosis", "WRKY"

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

Cancer Lett. 2020 Sep 28;488:50-62. Epub 2020 May 28
Shakti Ranjan Satapathy 1 , Anita Sjölander 2
Shakti Ranjan Satapathy 1 , Anita Sjölander 2

[No authors listed]

Author information
  • 1 Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
  • 2 Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden. Electronic address: anita.sjolander@med.lu.se.

摘要


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.

KEYWORDS: 5-FU, Colon cancer, CysLT(1)R, Drug resistance, Stemness, Zebrafish