Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling. Cell Rep 2019 Dec 10;29(11):3472-3487.e4
Date
12/12/2019Pubmed ID
31825830Pubmed Central ID
PMC6927555DOI
10.1016/j.celrep.2019.11.036Scopus ID
2-s2.0-85075997214 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
The vascular endothelial growth factor-A (VEGF-A)-VEGFR2 pathway drives tumor vascularization by activating proangiogenic signaling in endothelial cells (ECs). Here, we show that EC-sphingosine-1-phosphate receptor 1 (S1PR1) amplifies VEGFR2-mediated angiogenic signaling to enhance tumor growth. We show that cancer cells induce S1PR1 activity in ECs, and thereby, conditional deletion of S1PR1 in ECs (EC-S1pr1-/- mice) impairs tumor vascularization and growth. Mechanistically, we show that S1PR1 engages the heterotrimeric G-protein Gi, which amplifies VEGF-VEGFR2 signaling due to an increase in the activity of the tyrosine kinase c-Abl1. c-Abl1, by phosphorylating VEGFR2 at tyrosine-951, prolongs VEGFR2 retention on the plasmalemma to sustain Rac1 activity and EC migration. Thus, S1PR1 or VEGFR2 antagonists, alone or in combination, reverse the tumor growth in control mice to the level seen in EC-S1pr1-/- mice. Our findings suggest that blocking S1PR1 activity in ECs has the potential to suppress tumor growth by preventing amplification of VEGF-VEGFR2 signaling.
Author List
Balaji Ragunathrao VA, Anwar M, Akhter MZ, Chavez A, Mao Y, Natarajan V, Lakshmikanthan S, Chrzanowska-Wodnicka M, Dudek AZ, Claesson-Welsh L, Kitajewski JK, Wary KK, Malik AB, Mehta DAuthor
Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCells, Cultured
Endothelial Cells
Endothelium, Vascular
HEK293 Cells
Humans
Male
Mice
Neoplasms, Experimental
Neovascularization, Pathologic
Neuropeptides
Proto-Oncogene Proteins c-abl
Signal Transduction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
rac1 GTP-Binding Protein
