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Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling
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- Ragunathrao, Vijay Avin Balaji (author)
- Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA;Univ Illinois, Coll Med, Ctr Lung & Vasc Biol, Chicago, IL 60612 USA
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- Anwar, Mumtaz (author)
- Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA;Univ Illinois, Coll Med, Ctr Lung & Vasc Biol, Chicago, IL 60612 USA
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- Akhter, Md Zahid (author)
- Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA;Univ Illinois, Coll Med, Ctr Lung & Vasc Biol, Chicago, IL 60612 USA
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- (creator_code:org_t)
- CELL PRESS, 2019
- 2019
- English.
- In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 29:11, s. 3472-3487
- Journal article (peer-reviewed)
Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
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