Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
Adv Cancer Res. 2013;117:37-58. doi: 10.1016/B978-0-12-394274-6.00002-9.
Ceramide, a bioactive sphingolipid, is now at the forefront of cancer research. Classically, ceramide is thought to induce death, growth inhibition, and senescence in cancer cells. However, it is now clear that this simple picture of ceramide no longer holds true. Recent studies suggest that there are diverse functions of endogenously generated ceramides, which seem to be context dependent, regulated by subcellular/membrane localization and presence/absence of direct targets of these lipid molecules. For example, different fatty-acid chain lengths of ceramide, such as C(16)-ceramide that can be generated by ceramide synthase 6 (CerS6), have been implicated in cancer cell proliferation, whereas CerS1-generated C(18)-ceramide mediates cell death. The dichotomy of ceramides' function in cancer cells makes some of the metabolic enzymes of ceramide synthesis potential drug targets (such as Cers6) to prevent cancer growth in breast and head and neck cancers. Conversely, activation of CerS1 could be a new therapeutic option for the development of novel strategies against lung and head and neck cancers. This chapter focuses on recent discoveries about the mechanistic details of mainly de novo-generated ceramides and their signaling functions in cancer pathogenesis, and about how these mechanistic information can be translated into clinically relevant therapeutic options for the treatment of cancer.
神经酰胺是一种生物活性的鞘脂类物质，目前是癌症研究的前沿领域。经典理论认为，神经酰胺可诱导癌细胞死亡、生长抑制和衰老。然而，目前很明显，神经酰胺的这种简单作用模式已不再适用。最近的研究表明，内源性神经酰胺具有多种功能，这些功能似乎依赖于细胞环境，受到亚细胞/膜定位以及这些脂质分子直接靶标的存在或缺失的调节。例如，神经酰胺的不同脂肪酸链长度（如神经酰胺合酶 6（CerS6）产生的 C(16)-神经酰胺）与癌细胞增殖有关，而 CerS1 产生的 C(18)-神经酰胺介导细胞死亡。神经酰胺在癌细胞中的功能的这种二分法使得神经酰胺合成的一些代谢酶（如 CerS6）成为潜在的药物靶点，以阻止乳腺癌和头颈部癌症的生长。相反，CerS1 的激活可能是针对肺癌和头颈部癌症开发新治疗策略的新治疗选择。本章重点介绍关于从头合成的神经酰胺的机制细节及其在癌症发病机制中的信号功能的最新发现，以及如何将这些机制信息转化为治疗癌症的临床相关治疗选择。
