Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling

被引:55
作者
Ragunathrao, Vijay Avin Balaji [1 ,2 ]
Anwar, Mumtaz [1 ,2 ]
Akhter, Md Zahid [1 ,2 ]
Chavez, Alejandra [1 ,2 ]
Mao, De Yu [3 ]
Natarajan, Viswanathan [1 ,2 ,4 ]
Lakshmikanthan, Sribalaji [5 ]
Chrzanowska-Wodnicka, Magdalena [5 ]
Dudek, Arkadiusz Z. [4 ]
Claesson-Welsh, Lena [6 ]
Kitajewski, Jan K. [3 ]
Wary, Kishore K. [1 ,2 ]
Malik, Asrar B. [1 ,2 ]
Mehta, Dolly [1 ,2 ]
机构
[1] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA
[2] Univ Illinois, Coll Med, Ctr Lung & Vasc Biol, Chicago, IL 60612 USA
[3] Univ Illinois, Coll Med, Dept Physiol, Chicago, IL 60612 USA
[4] Univ Illinois, Coll Med, Dept Med, Chicago, IL 60612 USA
[5] Blood Ctr Wisconsin, Blood Res Inst, Milwaukee, WI 53226 USA
[6] Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden
关键词
NUCLEOTIDE EXCHANGE FACTOR; VASCULAR-PERMEABILITY; ENDOTHELIAL-CELLS; ANTI-VEGF; SPROUTING ANGIOGENESIS; SPHINGOSINE KINASE-1; IN-VIVO; ACTIVATION; INHIBITOR; ABL;
D O I
10.1016/j.celrep.2019.11.036
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 S1 PR1 activity in ECs, and thereby, conditional deletion of Si PR1 in ECs (EC-Slpr1(-/-) mice) impairs tumor vascularization and growth. Mechanistically, we show that S1 PR1 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, S1 PR1 or VEGFR2 antagonists, alone or in combination, reverse the tumor growth in control mice to the level seen in EC-Slpr1(-/-) mice. Our findings suggest that blocking S1 PR1 activity in ECs has the potential to suppress tumor growth by preventing amplification of VEGF-VEGFR2 signaling.
引用
收藏
页码:3472 / +
页数:20
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