α-fluoro-β-alanine functions as a β-arrestin1-biased ligand of S1PR2 to upregulate DPD expression in cancer cells.

Authors

Mingyong Tan, Hanbing Shao, Xinan Zhang, Yuyao Cheng, Zhimeng Sun, Ming Yang, Siyuan Mu, Weishi Liang, Bo Han, Xinfeng Wu, Xiaohui Liu, Yong Hai, Shuxiang Cui, Xianjun Qu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 30. Pages e2533427123. Jul 28, 2026. Epub Jul 20, 2026.

Abstract

α-fluoro-β-alanine (FBAL), a catabolite of the chemotherapeutic agent 5-fluorouracil (5-FU), has attracted significant attention due to its cardiotoxicity and neurotoxicity. However, its association with 5-FU resistance, a major obstacle in cancer treatment, has rarely been reported. In this study, FBAL was identified as a β-arrestin1-biased ligand of sphingosine 1-phosphate receptor 2 (S1PR2), which upregulates dihydropyrimidine dehydrogenase (DPD) expression and drives 5-FU resistance in colorectal cancer. Mechanistically, following exposure to FBAL, S1PR2, a G protein-coupled receptor (GPCR), is phosphorylated by recruiting G protein-coupled receptor kinase 6 (GRK6). Phosphorylated S1PR2 coupled with β-arrestin1, but not G proteins, to activate the MEK/ERK/AP-1 pathway and promote DPYD transcription. Ser343 was identified as the key phosphorylation site of S1PR2 using IP-MS analysis. This residue within the C-terminal domain mediates receptor interaction with β-arrestin-1 to activate the β-arrestin-1-dependent ERK pathway, as was confirmed in HCT116^S1PR2KO-ΔC cells and HCT116^{S1PR2KO-S343A} cells. In vivo, mice bearing orthotopic xenografts of HCT116^{S1PR2KO-S343A} cells exhibited significantly enhanced higher sensitivity to 5-FU treatment compared to those HCT116^S1PR2KO-WT cells following FBAL. Taken together, this study showed that exposure to FBAL induces S1PR2 phosphorylation at Ser343 within the C-terminal mediated by GRK6, activating the β-arrestin1-dependent ERK pathway to upregulate DPD expression. This study not only delineates a phosphorylation-dependent signaling pathway in chemoresistance but also establishes S1PR2 as a promising therapeutic target for overcoming 5-FU resistance in cancer.

PMID:
42475555
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.