文章：

癌细胞中的神经酰胺调控信号

Ceramide-orchestrated signalling in cancer cells

原文发布日期：2012-12-13

DOI: 10.1038/nrc3398

类型: Review Article

开放获取: 否

要点：

1. Ceramide is a sphingolipid consisting of sphingosine, an 18-carbon unsaturated amino alcohol hydrocarbon chain, which is joined by an amide linkage to a fatty acid of varying chain length and a varying degree of saturation. The type of fatty acyl group that is attached often dictates the biological activities of ceramide.
2. Through its capacity to induce programmed cell death (apoptosis), ceramide can function as a potent tumour suppressor lipid. Ceramide can also limit cancer cell proliferation by blocking cell cycle transition. Ceramide can also instigate autophagic responses in cancer cells; however, these may yield survival or lethal outcomes.
3. Cancer cells exert tight control over the metabolism of ceramide. As a survival mode, cancer cells upregulate enzymes that metabolize ceramide, which results in muted apoptotic responses and/or the promotion of mitogenicity, depending on the routes by which ceramide is metabolized.
4. Ceramide signalling in cancer cells enlists extrinsic signalling, which originates outside the cell, or intrinsic signalling (also known as the mitochondrial pathway) that originates from within the cell, to signal to downstream beacons of cellular response. These responses can be caspase (protease)-dependent or caspase-independent.
5. Key players in ceramide signalling in cancer are protein phosphatase 2A, p38, JUN N-terminal kinase (JNK), AKT, protein kinase Cζ (PKCζ) and survivin, proteins that communicate and reinforce tumour cell demise and/or the arrest of the cell cycle at G1 and G2 phases.
6. Because of its ability to induce apoptosis, ceramide holds promise as an anticancer agent. Ceramide-based therapies are being developed through the use of ceramide-generating agents, such as fenretinide, and by the use of exogenous cell-permeable short-chain ceramides, such as C6 ceramide. With both avenues, the effect of ceramide can be magnified by the inclusion of agents that block cancer cell-mediated elimination of ceramide.

要点翻译：

1. 神经酰胺是一种鞘脂，由鞘氨醇（一种18碳不饱和氨基醇烃链）通过酰胺键与链长度和饱和度各异的脂肪酸连接而成。附着的脂肪酰基类型通常决定神经酰胺的生物活性。
2. 通过诱导程序性细胞死亡（凋亡）的能力，神经酰胺可作为有效的肿瘤抑制脂质。它还能通过阻断细胞周期转换来限制癌细胞增殖。此外，神经酰胺可引发癌细胞的自噬反应，但这种反应可能促进生存或导致细胞死亡。
3. 癌细胞对神经酰胺代谢进行严格调控。作为一种生存模式，癌细胞会上调代谢神经酰胺的酶，这会导致凋亡反应减弱和/或促有丝分裂效应增强，具体取决于神经酰胺的代谢途径。
4. 癌细胞中的神经酰胺信号传导通过外部信号（源自细胞外）或内部信号（又称线粒体途径，源自细胞内）来传递至下游细胞反应信标。这些反应可能是caspase（蛋白酶）依赖性或不依赖性的。
5. 神经酰胺在癌症中信号传导的关键调控因子包括蛋白磷酸酶2A、p38、JUN N末端激酶（JNK）、AKT、蛋白激酶Cζ（PKCζ）和生存蛋白，这些蛋白质通过信号传递协同促进肿瘤细胞死亡和/或使细胞周期停滞在G1和G2期。
6. 由于其诱导凋亡的能力，神经酰胺有望成为抗癌剂。基于神经酰胺的疗法正在通过使用神经酰胺生成剂（如芬维A胺）和外源性细胞渗透性短链神经酰胺（如C6神经酰胺）进行开发。通过联合使用阻断癌细胞介导的神经酰胺清除的药物，可增强这两种途径中神经酰胺的效应。

英文摘要：

One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of a regulator of cell fate. Ceramide, it turns out, is a powerful tumour suppressor, potentiating signalling events that drive apoptosis, autophagic responses and cell cycle arrest. However, defects in ceramide generation and metabolism in cancer cells contribute to tumour cell survival and resistance to chemotherapy. This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide. The potential of ceramide-based therapeutics in the treatment of cancer is also discussed.

摘要翻译： 

癌症治疗进展的一个关键障碍，是无法控制细胞增殖与凋亡之间的平衡：这时，神经酰胺登场了。过去15年的发现已将这种鞘脂提升至决定细胞命运的高度。事实证明，神经酰胺是一种强效的肿瘤抑制因子，能增强驱动凋亡、自噬反应和细胞周期停滞的信号事件。然而，癌细胞中神经酰胺生成与代谢的缺陷，却促进了肿瘤细胞的存活并导致化疗耐药。本综述聚焦于神经酰胺信号传导，以及通过靶向特定代谢节点来放大其肿瘤抑制活性。文中还探讨了基于神经酰胺的疗法在癌症治疗中的潜力。

原文链接：

Ceramide-orchestrated signalling in cancer cells