PUBLICATION
S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720
- Authors
- Laroche, F.J.F., Li, S., Shen, N., Hwang, S.K., Nguyen, G., Yu, W., Wong, C.K., Quinton, R.J., Berman, J.N., Liu, C.T., Singh, A., Ganem, N.J., Thiagalingam, S., Feng, H.
- ID
- ZDB-PUB-230414-59
- Date
- 2023
- Source
- Cells 12(7): (Journal)
- Registered Authors
- Berman, Jason
- Keywords
- FTY720, MK2206, invasiveness, sphingosine 1-phosphate receptor 1, threonine 236 phosphorylation, triple-negative breast cancer, zebrafish
- MeSH Terms
-
- Animals
- Fingolimod Hydrochloride*/pharmacology
- Humans
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism
- Receptors, Lysosphingolipid/metabolism
- Sphingosine-1-Phosphate Receptors*/metabolism
- Threonine
- Triple Negative Breast Neoplasms*/drug therapy
- Zebrafish/metabolism
- PubMed
- 37048053 Full text @ Cells
Citation
Laroche, F.J.F., Li, S., Shen, N., Hwang, S.K., Nguyen, G., Yu, W., Wong, C.K., Quinton, R.J., Berman, J.N., Liu, C.T., Singh, A., Ganem, N.J., Thiagalingam, S., Feng, H. (2023) S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720. Cells. 12(7):.
Abstract
Hyperactive sphingosine 1-phosphate (S1P) signaling is associated with a poor prognosis of triple-negative breast cancer (TNBC). Despite recent evidence that links the S1P receptor 1 (S1P1) to TNBC cell survival, its role in TNBC invasion and the underlying mechanisms remain elusive. Combining analyses of human TNBC cells with zebrafish xenografts, we found that phosphorylation of S1P receptor 1 (S1P1) at threonine 236 (T236) is critical for TNBC dissemination. Compared to luminal breast cancer cells, TNBC cells exhibit a significant increase of phospho-S1P1 T236 but not the total S1P1 levels. Misexpression of phosphorylation-defective S1P1 T236A (alanine) decreases TNBC cell migration in vitro and disease invasion in zebrafish xenografts. Pharmacologic disruption of S1P1 T236 phosphorylation, using either a pan-AKT inhibitor (MK2206) or an S1P1 functional antagonist (FTY720, an FDA-approved drug for treating multiple sclerosis), suppresses TNBC cell migration in vitro and tumor invasion in vivo. Finally, we show that human TNBC cells with AKT activation and elevated phospho-S1P1 T236 are sensitive to FTY720-induced cytotoxic effects. These findings indicate that the AKT-enhanced phosphorylation of S1P1 T236 mediates much of the TNBC invasiveness, providing a potential biomarker to select TNBC patients for the clinical application of FTY720.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping