Publication Date
10-1-2024
Journal
World Journal of Clinical Oncology
DOI
10.14740/wjon1890
PMID
39328328
PMCID
PMC11424120
PubMedCentral® Posted Date
9-16-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Colorectal cancer, Epithelial-to-mesenchymal transition, Sphingosine, Chemotherapy resistance, Cancer stem cells, Colorectal cancer, Epithelial-to-mesenchymal transition, Sphingosine, Chemotherapy resistance, Cancer stem cells
Abstract
BACKGROUND: Epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), and colorectal cancer (CRC) therapy resistance are closely associated. Prior reports have demonstrated that sphingosine-1-phosphate (S1P) supports stem cells and maintains the CSC phenotype. We hypothesized that the EMT inducer SNAI1 drives S1P signaling to amplify CSC self-renewal capacity and chemoresistance.
METHODS: CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. The therapeutic ability of sphingosine kinase 2 (SPHK2) was assessed using siRNA and ABC294640, a SPHK2 inhibitor. CSCs were isolated from patient-derived xenografts (PDXs) and assessed for SPHK2 and SNAI1 expression.
RESULTS: Ectopic SNAI1 expressing cell lines demonstrated elevated SPHK2 expression and increased SPHK2 promoter activity. SPHK2 inhibition with siRNA or ABC294640 ablated
CONCLUSIONS: SNAI1/SPHK2 signaling mediates cancer stemness and 5FU resistance, implicating S1P as a therapeutic target for CRC. The S1P inhibitor ABC294640 holds potential as a therapeutic agent to target CSCs in therapy refractory CRC.
Included in
Digestive System Diseases Commons, Gastroenterology Commons, Medical Sciences Commons, Mental and Social Health Commons, Oncology Commons, Surgery Commons