Targeting S1PR1 in Thyroid Cancer: Functional Characterization and Proteasome‐Mediated Suppression by Quercetin

ABSTRACT Sphingosine‐1‐phosphate receptor 1 (S1PR1, also known as EDG1) is a G‐protein‐coupled receptor. Although there have been conflicting results reported, S1PR1 is generally accepted to be protumorigenic in many cancer types. However, S1PR1 has not been studied in thyroid cancer. This study aimed to investigate the biological activity of S1PR1 in thyroid cancer. S1PR1 protein levels were found to be higher in thyroid cancer tissues than adjacent normal tissues. Using an S1PR1‐GFP construct, we showed that S1PR1 is localized in the cell membrane; however, when stimulated by sphingosine‐1‐phosphate, S1PR1 appeared to move inside in the cells. In functional studies, S1PR1 knock‐out cells generated using the CRISPR/Cas9 system exhibited reduced S1PR1 activity, including colony formation, cell migration, and cell invasion. This was accompanied by the inhibition of STAT3, ERK1/2, and AKT kinase activity and cell adhesion protein expression. Furthermore, we screened several anticancer compounds to determine their effects on S1PR1 expression levels in thyroid cancer cells and found that quercetin significantly reduced S1PR1 protein levels in these cells. Overall, our results indicated that S1PR1 expression at the protein level has a positive relationship with thyroid cancer progression, as seen in other cancers. These data also suggest that quercetin is a potential anticancer drug that can target S1PR1‐positive cells.