Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
Biochem Soc Trans. 2012 Feb;40(1):94-100. doi: 10.1042/BST20110602.
There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1-S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin-proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor-receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression.
越来越多的证据表明，生物活性脂质 S1P（鞘氨醇 1-磷酸）在癌症中起着关键作用。S1P 由许多酶合成和代谢，包括鞘氨醇激酶、S1P 裂合酶和 S1P 磷酸酶。S1P 通过与细胞表面 G 蛋白偶联受体（S1P1-S1P5）结合来引发细胞反应，也可以通过直接结合来调节许多细胞内靶标，如 HDAC（组蛋白去乙酰化酶）1/2，从而诱导表观遗传调控。S1P 参与癌症进展，包括细胞转化/致癌、细胞存活/凋亡、细胞迁移/转移和肿瘤微环境新生血管形成。在本文中，我们描述了我们关于肿瘤中鞘氨醇激酶 1 和 S1P 受体表达与临床结果的相关性的研究发现，并定义了一些分子机制，这些机制涉及鞘氨醇激酶 1 和 S1P 受体在形成癌细胞迁移表型中的作用。鞘氨醇激酶 1 在获得化疗耐药性中的作用以及 S1P 受体与 HER2 等癌基因的相互作用也得到了综述。我们还讨论了鞘氨醇激酶 1 的小分子抑制剂在变构、鞘氨醇激酶 1 的泛素-蛋白酶体降解和抗癌活性方面的新方面。最后，我们描述了 S1P 受体调节剂如何消除 S1P 受体-受体酪氨酸激酶相互作用，从而有可能抑制生长因子依赖性癌症进展。
