G protein-coupled sphingosine-1-phosphate receptors: potential molecular targets for angiogenic and anti-angiogenic therapies

N. Takuwa, Y. Okamoto, K. Yoshioka, Y. Takuwa
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引用次数: 3

Abstract

Sphingosine-1-phosphate (S1P) is a plasma lipid mediator with pleiotropic activities; it is constitutively produced in red blood cells and vascular endothelial cells through phosphorylation of sphingosine by one of two S1P synthesizing enzymes, sphingosine kinase 1 and 2 (SphK 1, 2), and exported into plasma to bind to high density lipoprotein and albumin. Sphingosine-1-phosphate acts through five members of the G protein-coupled S1P receptors (S1PR1-S1PR5) to exert diverse actions, which include vascular maturation in embryonic stage and postnatal angiogenesis, maintenance of functional integrity of vascular endothelium, regulation of vascular tonus, and lymphocyte trafficking. Sphingosine-1-phosphate is unique in its ability to regulate cell migration either positively or negatively by acting through different receptor subtypes. S1PR1 and S1PR3 mediate chemotactic cell migration toward S1P via Gi/Rac pathway, whereas S1PR2 mediates S1P inhibition of chemotaxis via G12/13/Rho-dependent inhibition of Rac. Sphingosine-1-phosphate positively or negatively regulates tumor cell migration, invasion in Matrigel, and hematogenous metastasis in manners strictly dependent on S1P receptor subtypes expressed in tumor cells. S1PR1 (and S1PR3) also mediates activation of Gi/phosphatidylinositol 3-kinase (PI3K)/Akt and stimulation of cell proliferation/survival, whereas S1PR2 could mediate suppression of cell proliferation/survival through G12/13/Rho/Rho kinase/PTEN-dependent Akt inhibition. S1PR1 (and S1PR3) expressed in endothelial cells mediates angiogenic action of S1P by stimulating endothelial cell migration, proliferation and tube formation. In a mouse model of hindlimb ischemia after femoral artery resection, repeated local administration or sustained delivery of S1P, or transgenic overexpression of SphK1, accelerates post-ischemic angiogenesis, through the S1P actions on both endothelial cells and bone marrow-derived myeloid cells (BMDCs). In tumor cells, SphK1 is upregulated especially in advanced stages, through mechanisms involving both activating Ras mutation and hypoxia, which leads to increased S1P production and also decreased cellular content of pro-apoptotic sphingolipid ceramide, a metabolic precursor of S1P. Apoptotic tumor cells also produce S1P through SphK2 activation, thus implicated in tumor angiogenesis by acting on endothelial cells through S1PR1/S1PR3, as well as tumor-infiltrating macrophages and BMDCs. Inhibition of S1PR1 function by either an anti-S1P antibody or FTY720 inhibits tumor angiogenesis and tumor growth. Differently from S1PR1, S1PR2 expressed in host cells mediates inhibition of tumor angiogenesis and tumor growth, through mechanisms involving the suppression of endothelial cell migration, proliferation and tube formation, and inhibition of BMDC recruitment to tumor stroma with suppressed expression of pro-angiogenic factor and matrix metalloprotease 9. These findings provide the molecular basis for S1P receptor subtype-selective targeting strategies aiming at angiogenic therapy for occlusive peripheral arterial diseases, and anti-angiogenic and anti-tumor therapies against cancer. Biomedical Reviews 2011; 22: 15-29.
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G蛋白偶联鞘氨醇-1-磷酸受体:血管生成和抗血管生成治疗的潜在分子靶点
鞘氨醇-1-磷酸(S1P)是一种多效性的血浆脂质介质;S1P合成酶sphingosine kinase 1和2 (sphk1,2)中的一种磷酸化sphingosine,从而在红细胞和血管内皮细胞中组成性地产生sphingosine,并输出到血浆中与高密度脂蛋白和白蛋白结合。鞘氨醇-1-磷酸通过G蛋白偶联S1P受体的5个成员(S1PR1-S1PR5)发挥多种作用,包括胚胎期血管成熟和出生后血管生成、维持血管内皮功能完整性、调节血管张力和淋巴细胞运输。鞘氨醇-1-磷酸通过不同的受体亚型积极或消极地调节细胞迁移的能力是独一无二的。S1PR1和S1PR3通过Gi/Rac途径介导趋化细胞向S1P迁移,而S1PR2通过G12/13/ rho依赖的Rac抑制作用介导S1P趋化。鞘氨醇-1-磷酸正或负调节肿瘤细胞的迁移、侵袭基质和血行转移,其方式严格依赖于肿瘤细胞中表达的S1P受体亚型。S1PR1(和S1PR3)也介导Gi/磷脂酰肌醇3-激酶(PI3K)/Akt的激活和刺激细胞增殖/存活,而S1PR2可以通过G12/13/Rho/Rho激酶/ pten依赖性Akt抑制介导细胞增殖/存活的抑制。内皮细胞中表达的S1PR1(和S1PR3)通过刺激内皮细胞迁移、增殖和成管,介导S1P的血管生成作用。在股动脉切除后后肢缺血小鼠模型中,反复局部给药或持续递送S1P,或转基因过表达SphK1,通过S1P对内皮细胞和骨髓源性髓样细胞(bmdc)的作用,加速缺血后血管生成。在肿瘤细胞中,SphK1表达上调,尤其是在晚期,其机制包括激活Ras突变和缺氧,从而导致S1P的产生增加,并降低细胞中促凋亡鞘脂神经酰胺(S1P的代谢前体)的含量。凋亡的肿瘤细胞也通过活化SphK2产生S1P,从而通过S1PR1/S1PR3作用于内皮细胞,以及肿瘤浸润性巨噬细胞和BMDCs参与肿瘤血管生成。通过抗s1p抗体或FTY720抑制S1PR1功能可抑制肿瘤血管生成和肿瘤生长。与S1PR1不同,宿主细胞中表达的S1PR2通过抑制促血管生成因子和基质金属蛋白酶9的表达,抑制内皮细胞的迁移、增殖和管的形成,抑制BMDC向肿瘤基质的募集,从而抑制肿瘤血管生成和肿瘤生长。这些发现为S1P受体亚型选择性靶向策略针对闭塞性外周动脉疾病的血管生成治疗,以及抗血管生成和抗肿瘤治疗癌症提供了分子基础。生物医学评论2011;22: 15 - 29。
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