文章：

鞘脂代谢在癌症信号传导和治疗中的作用

Sphingolipid metabolism in cancer signalling and therapy

原文发布日期：2017-11-17

DOI: 10.1038/nrc.2017.96

类型: Review Article

开放获取: 否

要点：

1. Sphingolipids are bioactive molecules that have key roles in the regulation of cancer cell signalling to control tumour suppression or survival. Ceramide is a bioeffector molecule that mediates cell death, whereas sphingosine-1-phosphate (S1P) induces tumour cell proliferation, resistance to chemotherapy, radiotherapy or immunotherapy and metastasis.
2. The metabolic network of sphingolipids provides regulatory nodes for controlling cancer growth and/or proliferation in response to cellular stress, including the activation of enzymes that generate the tumour suppressor ceramide and/or inhibit the conversion of ceramide to S1P or other complex sphingolipids that have pro-survival and/or anti-apoptotic function, such as sphingomyelin and glucosylceramide.
3. Induction of ceramide generation and/or accumulation mediates cancer cell death via apoptosis, necroptosis or mitophagy, which might be regulated by the distinct functions of de novo-generated endogenous ceramides with different fatty acyl chain lengths. Downstream mechanisms of ceramide in induction of cell death are regulated mainly by its subcellular localization, trafficking and lipid–protein binding between ceramide and target proteins such as phosphatase 2A inhibitor I2PP2A or microtubule-associated protein 1 light chain 3β (LC3B) in cancer cells.
4. The metabolic conversion of ceramide to S1P increases cancer cell survival via G protein-coupled S1P receptor (S1PR)-dependent or S1PR-independent oncogenic signalling. Systemic S1P mediates host–cancer cell communication to increase tumour metastasis, which involves the function of protein spinster homologue 2 (SPNS2) for S1P secretion from lymphoid endothelial cells and S1PR1-dependent or S1PR2-dependent signalling in cancer cells to induce migration and/or evade immune-cell-mediated cytotoxicity.
5. There are also receptor-independent roles of endogenous S1P; direct S1P–protein interactions, including with histone deacetylase 1 (HDAC1), HDAC2 and telomerase, regulate cancer cell growth and proliferation.
6. Targeting sphingolipid metabolism to activate pro-cell death ceramide signalling and/or inhibit pro-survival S1P signalling using genetic, molecular, immunological or pharmacological tools provides novel strategies for the development of new therapies — including immunotherapies — for various cancer types, some of which are under current evaluation in active clinical trials.

要点翻译：

1. 鞘脂是一类生物活性分子，在调控癌细胞信号传导以抑制肿瘤或促进存活方面具有关键作用。神经酰胺作为生物效应分子可介导细胞死亡，而1-磷酸鞘氨醇（S1P）则诱导肿瘤细胞增殖、增强对化疗、放疗或免疫治疗的抵抗能力并促进转移。
2. 鞘脂代谢网络通过调控节点控制癌症生长和/或增殖以应对细胞应激，包括激活生成肿瘤抑制因子神经酰胺的酶，和/或抑制神经酰胺转化为具有促存活和/或抗凋亡功能的S1P或其他复杂鞘脂（如鞘磷脂和葡萄糖神经酰胺）。
3. 诱导神经酰胺生成和/或积累可通过凋亡、坏死性凋亡或线粒体自噬介导癌细胞死亡，这一过程可能受新生成的不同脂酰链长度的内源性神经酰胺的特异功能调控。神经酰胺诱导细胞死亡的下游机制主要受其亚细胞定位、转运及其与靶蛋白（如癌细胞中的磷酸酶2A抑制剂I2PP2A或微管相关蛋白1轻链3β）之间的脂质-蛋白结合作用调控。
4. 神经酰胺代谢转化为S1P可通过G蛋白偶联S1P受体依赖性或非依赖性致癌信号增强癌细胞存活。系统性S1P介导宿主-癌细胞通讯以促进肿瘤转移，该过程涉及蛋白Spinster同源物2介导淋巴管内皮细胞分泌S1P，以及癌细胞中S1PR1或S1PR2依赖性信号通路诱导迁移和/或逃避免疫细胞介导的细胞毒性。
5. 内源性S1P还存在受体非依赖性功能：通过直接S1P-蛋白相互作用（包括与组蛋白去乙酰化酶1、HDAC2和端粒酶的结合）调控癌细胞生长与增殖。
6. 通过遗传、分子、免疫或药理学手段靶向鞘脂代谢，以激活促细胞死亡神经酰胺信号和/或抑制促存活S1P信号，为开发新型疗法（包括免疫疗法）提供了创新策略。目前针对多种癌症类型的相关疗法正在积极临床试验中进行评估。

英文摘要：

Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

摘要翻译： 

鞘脂类，包括两种核心生物活性脂质——神经酰胺（ceramide）与1-磷酸鞘氨醇（S1P），分别在调控癌细胞死亡与存活中起相反作用。近年来，关于鞘脂代谢及信号如何响应抗癌治疗并调控这些过程的研究取得令人振奋的进展。借助创新性的分子、遗传及药理学工具，靶向癌细胞内鞘脂信号节点，最新研究揭示了鞘脂及其下游靶点在调控肿瘤生长以及对化疗、放疗和/或免疫治疗反应中的机制细节。例如，基于结构-功能的研究为开发基于机制的抗癌治疗策略提供了新契机，旨在恢复抗增殖的神经酰胺信号和/或抑制促存活的S1P–S1P受体（S1PR）信号。本文综述了神经酰胺诱导的细胞应激如何通过诱导凋亡、坏死性凋亡和/或线粒体自噬等多种机制介导癌细胞死亡；同时重点介绍了神经酰胺经鞘氨醇激酶1和2代谢生成S1P的过程，以及S1P通过依赖S1PR或非受体依赖信号通路影响癌细胞生长、耐药和肿瘤转移的作用。最后，还介绍了靶向鞘脂代谢和/或信号酶的研究及其改善癌症治疗的临床意义。

原文链接：

Sphingolipid metabolism in cancer signalling and therapy