Institute of General Pharmacology and Toxicology, University Hospital and Goethe University Frankfurt, Germany.
Department of Neurology, University Hospital, RWTH Aachen, Germany.
FEBS J. 2022 Sep;289(18):5670-5681. doi: 10.1111/febs.16446. Epub 2022 Apr 3.
Sphingosine 1-phosphate (S1P) is a lipid mediator with numerous biological functions. The term 'S1P' mainly refers to the sphingolipid molecule with a long-chain sphingoid base of 18 carbon atoms, d18:1 S1P. The enzyme serine palmitoyltransferase catalyses the first step of the sphingolipid de novo synthesis using palmitoyl-CoA as the main substrate. After further reaction steps, d18:1 S1P is generated. However, also stearyl-CoA or myristoyl-CoA can be utilised by the serine palmitoyltransferase, which at the end of the S1P synthesis pathway, results in the production of d20:1 S1P and d16:1 S1P respectively. We measured these S1P homologues in mice and renal tissue of patients suffering from renal cell carcinoma (RCC). Our experiments highlight the relevance of d16:1 S1P for the induction of connective tissue growth factor (CTGF) in the human renal clear cell carcinoma cell line A498 and human RCC tissue. We show that d16:1 S1P versus d18:1 and d20:1 S1P leads to the highest CTGF induction in A498 cells via S1P2 signalling and that both d16:1 S1P and CTGF levels are elevated in RCC compared to adjacent healthy tissue. Our data indicate that d16:1 S1P modulates conventional S1P signalling by acting as a more potent agonist at the S1P2 receptor than d18:1 S1P. We suggest that elevated plasma levels of d16:1 S1P might play a pro-carcinogenic role in the development of RCC via CTGF induction.
鞘氨醇 1-磷酸（S1P）是一种具有多种生物学功能的脂质介质。“S1P”一词主要指具有 18 个碳原子长链神经酰胺的鞘脂分子，即 d18:1 S1P。丝氨酸棕榈酰转移酶利用棕榈酰-CoA 作为主要底物催化鞘脂从头合成的第一步。经过进一步的反应步骤，生成 d18:1 S1P。然而，丝氨酸棕榈酰转移酶也可以利用硬脂酰-CoA 或肉豆蔻酰-CoA，最终在 S1P 合成途径的末端分别产生 d20:1 S1P 和 d16:1 S1P。我们在患有肾细胞癌（RCC）的小鼠和患者的肾组织中测量了这些 S1P 同系物。我们的实验强调了 d16:1 S1P 在诱导人肾透明细胞癌细胞系 A498 和人 RCC 组织中的结缔组织生长因子（CTGF）中的相关性。我们表明，与 d18:1 和 d20:1 S1P 相比，d16:1 S1P 通过 S1P2 信号导致 A498 细胞中 CTGF 的诱导最高，并且与相邻健康组织相比，RCC 中 d16:1 S1P 和 CTGF 的水平均升高。我们的数据表明，d16:1 S1P 通过作为 S1P2 受体的比 d18:1 S1P 更强效的激动剂来调节传统的 S1P 信号，从而调节 S1P 信号。我们建议，d16:1 S1P 水平升高可能通过诱导 CTGF 在 RCC 的发展中发挥致癌作用。
