Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling
Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling
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DOI：
10.1016/j.celrep.2019.11.036
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发表时间：
2019-12-10
期刊：
影响因子：
8.8
通讯作者：
Mehta, Dolly
中科院分区：
文献类型：
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作者：
Ragunathrao, Vijay Avin Balaji;Anwar, Mumtaz;Mehta, Dolly
血管内皮生长因子-A (VEGF-A)-VEGFR2 通路通过激活内皮细胞 (EC) 中的促血管生成信号传导来驱动肿瘤血管化。在这里，我们发现 EC-1-磷酸鞘氨醇受体 1 (S1PR1) 放大 VEGFR2 介导的血管生成信号，从而增强肿瘤生长。我们发现癌细胞在 EC 中诱导 S1 PR1 活性，因此，EC 中 Si PR1 的条件性缺失（EC-Slpr1(-/-) 小鼠）会损害肿瘤血管化和生长。从机制上讲，我们表明 S1 PR1 与异源三聚体 G 蛋白 Gi 结合，由于酪氨酸激酶 c-Abl1 活性的增加，Gi 放大了 VEGF-VEGFR2 信号传导。 c-Abl1 通过在酪氨酸 951 位点磷酸化 VEGFR2，延长 VEGFR2 在质膜上的保留时间，以维持 Rac1 活性和 EC 迁移。因此，S1 PR1或VEGFR2拮抗剂，单独或组合，将对照小鼠中的肿瘤生长逆转至EC-Slpr1(-/-)小鼠中观察到的水平。我们的研究结果表明，阻断 EC 中的 S1 PR1 活性有可能通过阻止 VEGF-VEGFR2 信号放大来抑制肿瘤生长。
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.