文章：

鞘氨醇1-磷酸和癌症

Sphingosine 1-phosphate and cancer

原文发布日期：2010-06-17

DOI: 10.1038/nrc2875

类型: Review Article

开放获取: 否

要点：

1. Sphingosine 1-phosphate (S1P) is a biologically active lipid that promotes tumour growth, neovascularization and inflammation. It regulates the growth, survival and migration of mammalian cells through both intracellular and receptor-mediated mechanisms.
2. S1P is formed by the sphingosine kinase (SK)-catalysed phosphorylation of sphingosine. There are two isoforms of SK, SK1 and SK2.
3. SK1 promotes V12Ras-dependent transformation, and the growth and survival of cancer cells, while inhibiting apoptosis and conferring resistance to γ-irradiation and chemotherapeutic agents.
4. No mutations linked with cancer have been identified in SK1. However, cancer cells demonstrate a reliance on this enzyme for cell growth and survival, that is, a non-oncogenic addiction for SK1.
5. SK1 expression is increased in several types of human tumours compared with normal tissue and, in some cases, this is correlated with disease progression and reduced patient survival.
6. A ceramide–sphingosine–S1P rheostat exists in cells. Ceramide and sphingosine are pro-apoptotic, whereas S1P promotes cell survival. Agents that regulate the interconversion of ceramide–sphingosine–S1P can direct the cell towards either an apoptotic or a survival programme depending on the relative position of the rheostat.
7. The sensitivity of cancer cells to chemotherapeutic agents is a function of the activities of SK (which produces S1P) and S1P lyase and S1P phosphatases (which remove S1P).
8. S1P stimulates S1P-specific plasma membrane G protein-coupled receptors (S1PR_1–5). S1PR₁ and S1PR₃ generally promote migration and cell survival, whereas S1PR₂ is generally inhibitory for migration.
9. S1P receptors crosstalk with receptor tyrosine kinases to regulate tumorigenesis and neovascularization. This includes S1P-dependent transactivation of receptor tyrosine kinases, the formation of functional receptor tyrosine kinase–S1P receptor complexes and the amplification of regulatory loops.
10. Solid tumours are often oxygen insufficient and express hypoxia-inducible factors. In this regard, hypoxia increases SK1 and SK2 expression to promote neovascularization of the tumour.
11. Anticancer therapeutics in development include S1P-specific neutralizing antibodies (such as ASONEP), SK inhibitors and functional S1P receptor antagonists, which may mitigate the hyperproliferative, migratory and inflammatory components of cancer.

要点翻译：

1. 鞘氨醇-1-磷酸（S1P）是一种具有生物活性的脂质，能促进肿瘤生长、新生血管形成及炎症反应。它通过细胞内机制和受体介导机制共同调控哺乳动物细胞的生长、存活与迁移。
2. S1P由鞘氨醇激酶（SK）催化鞘氨醇磷酸化形成。SK存在两种亚型：SK1与SK2。
3. SK1可促进V12Ras依赖性转化及癌细胞生长存活，同时抑制细胞凋亡，并赋予细胞对γ辐射和化疗药物的耐药性。
4. 目前尚未发现SK1存在与癌症相关的突变。然而，癌细胞表现出对该酶的生长存活依赖性，即对SK1的非致癌性成瘾。
5. 与正常组织相比，SK1在多种人类肿瘤中表达升高，且在某些病例中与疾病进展及患者生存率降低相关。
6. 细胞内存在神经酰胺-鞘氨醇-S1P平衡调控机制。神经酰胺与鞘氨醇促进细胞凋亡，而S1P则支持细胞存活。调控三者相互转化的物质可根据平衡点的相对位置，引导细胞走向凋亡或存活程序。
7. 癌细胞对化疗药物的敏感度取决于SK（合成S1P）与S1P裂解酶、S1P磷酸酯酶（清除S1P）的活性平衡。
8. S1P可刺激S1P特异性质膜G蛋白偶联受体（S1PR1-5）。S1PR1和S1PR3通常促进细胞迁移与存活，而S1PR2则主要抑制迁移过程。
9. S1P受体与受体酪氨酸激酶发生交叉对话，共同调控肿瘤发生与新生血管形成。这包括S1P依赖性受体酪氨酸激酶反式激活、功能性受体酪氨酸激酶-S1P受体复合物的形成，以及调控回路的放大效应。
10. 实体瘤常存在缺氧状态并表达缺氧诱导因子。在此背景下，缺氧环境会增强SK1与SK2的表达，促进肿瘤新生血管生成。
11. 正在研发的抗癌疗法包括S1P特异性中和抗体（如ASONEP）、SK抑制剂及功能性S1P受体拮抗剂，这些药物可能抑制癌症的过度增殖、迁移及炎症成分。

英文摘要：

There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer. S1P regulates processes such as inflammation, which can drive tumorigenesis; neovascularization, which provides cancer cells with nutrients and oxygen; and cell growth and survival. This occurs at multiple levels and involves S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase. This Review summarizes current research findings and examines the potential for new therapeutics designed to alter S1P signalling and function in cancer.

摘要翻译： 

有大量证据表明，鞘氨醇-1-磷酸（S1P）与癌症相关。S1P可调节炎症、新生血管形成、细胞生长与存活等过程——炎症可驱动肿瘤发生，新生血管为癌细胞提供营养与氧气。这些作用发生在多个层面，涉及S1P受体、鞘氨醇激酶、S1P磷酸酶及S1P裂解酶。本文综述了当前的研究发现，并探讨了通过干预S1P信号传导及其功能来开发癌症新疗法的潜力。

原文链接：

Sphingosine 1-phosphate and cancer