Tumor-suppressive sphingosine-1-phosphate receptor-2 counteracting tumor-promoting sphingosine-1-phosphate receptor-1 and sphingosine kinase 1 - Jekyll Hidden behind Hyde.
Tumor-suppressive sphingosine-1-phosphate receptor-2 counteracting tumor-promoting sphingosine-1-phosphate receptor-1 and sphingosine kinase 1 - Jekyll Hidden behind Hyde.
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发表时间：
2011
影响因子：
5.3
通讯作者：
N. Takuwa;Wa Du;E. Kaneko;Y. Okamoto;K. Yoshioka;Y. Takuwa
中科院分区：
文献类型：
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作者：
N. Takuwa;Wa Du;E. Kaneko;Y. Okamoto;K. Yoshioka;Y. Takuwa
鞘氨醇-1-磷酸（S1P）是一种血浆脂质介质，在哺乳动物发育、生理和病理生理中具有多种作用。它主要由红细胞通过鞘氨醇激酶1 （SphK1）的作用产生，导致血浆中高（约0.5微摩尔）稳态的S1P含量和血浆/淋巴/组织间质液之间陡峭的S1P浓度梯度。S1P也由活化的血小板和肿瘤细胞局部产生，在后者的情况下，SphK1是活化的Ras突变体和缺氧的下游靶点，并且经常上调，特别是在肿瘤晚期。大多数（如果不是全部的话）脊椎动物的S1P作用是通过进化保守的G蛋白偶联S1P受体家族介导的。普遍表达的哺乳动物亚型S1PR1、S1PR2和S1PR3通过偶联不同的异源三聚体G蛋白，介导S1P在不同细胞类型中的多效性作用。S1PR1和S1PR3通过偶联G(i)和激活Rac（细胞迁移所必需的Rho家族小G蛋白）介导细胞向S1P的定向迁移。事实上，S1PR1在淋巴细胞中的表达指导其从淋巴结进入淋巴和再循环，作为免疫抑制剂FTY720 （fingolimod）下调的靶点。内皮细胞中的S1PR1在胚胎期血管成熟中起重要作用，并介导S1P的血管生成和血管保护作用，包括eNOS激活和屏障完整性的维持。宿主内皮细胞和肿瘤细胞中表达的S1PR1和SphK1可能在旁分泌环中协同作用，促进肿瘤血管生成、肿瘤侵袭和进展。与之形成鲜明对比的是，S1PR2在G（12/13）介导的Rho激活的下游位点介导S1P对Rac的抑制，因此被鉴定为第一个负调控Rac和细胞迁移的G蛋白偶联受体。S1PR2还可以通过Rho-ROCK-PTEN通路介导Akt和细胞增殖/存活信号的抑制。在肿瘤细胞中表达的S1PR2介导了体外细胞迁移侵袭和体内转移的抑制。此外，S1PR2在宿主内皮细胞和肿瘤浸润性髓细胞中协同表达，通过抑制VEGF表达和MMP9活性，在体内介导肿瘤血管生成和肿瘤生长的有效抑制。这些最新发现为S1P受体亚型特异性、个体化治疗癌症患者提供了新的治疗策略。
Sphingosine-1-phosphate (S1P) is a plasma lipid mediator with multiple roles in mammalian development, physiology and pathophysiology. It is constitutively produced mostly by erythrocytes by the action of sphingosine kinase 1 (SphK1), resulting in high (∼0.5 micromolar) steady-state plasma S1P content and steep S1P concentration gradient imposed between plasma/lymph/tissue interstitial fluid. S1P is also locally produced by activated platelets and tumor cells, in the latter case SphK1 is a downstream target of activated Ras mutant and hypoxia, and is frequently upregulated especially in advanced stages of tumors. Most if not all of the S1P actions in vertebrates are mediated through evolutionarily conserved G protein-coupled S1P receptor family. Ubiquitously expressed mammalian subtypes S1PR1, S1PR2 and S1PR3 mediate pleiotropic actions of S1P in diverse cell types, through coupling to distinctive repertoire of heterotrimeric G proteins. S1PR1 and S1PR3 mediate directed cell migration toward S1P through coupling to G(i) and activating Rac, a Rho family small G protein essential for cell migration. Indeed, S1PR1 expressed in lymphocytes directs their egress from lymph nodes into lymph and recirculation, serving as the target for downregulation by the immunosuppressant FTY720 (fingolimod). S1PR1 in endothelial cells plays an essential role in vascular maturation in embryonic stage, and mediates angiogenic and vascular protective roles of S1P which include eNOS activation and maintenance of barrier integrity. It is likely that S1PR1 and SphK1 expressed in host endothelial cells and tumor cells act in concert in a paracrine loop to contribute to tumor angiogenesis, tumor invasion and progression. In sharp contrast, S1PR2 mediates S1P inhibition of Rac at the site downstream of G(12/13)-mediated Rho activation, thus identified as the first G protein-coupled receptor that negatively regulates Rac and cell migration. S1PR2 could also mediate inhibition of Akt and cell proliferation/survival signaling via Rho-ROCK-PTEN pathway. S1PR2 expressed in tumor cells mediates inhibition of cell migration and invasion in vitro and metastasis in vivo. Moreover, S1PR2 expressed in host endothelial cells and tumor-infiltrating myeloid cells in concert mediates potent inhibition of tumor angiogenesis and tumor growth in vivo, with inhibition of VEGF expression and MMP9 activity. These recent findings provide further basis for S1P receptor subtype-specific, novel therapeutic tactics for individualized treatment of patients with cancer.