Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
Future Oncol. 2010 Oct;6(10):1603-24. doi: 10.2217/fon.10.116.
Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in the world. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. Interestingly, recent studies suggest de novo-generated ceramides may have distinct and opposing roles in the promotion/suppression of tumors, and that these activities are based on their fatty acid chain lengths, subcellular localization and/or direct downstream targets. For example, in head and neck cancer cells, ceramide synthase 6/C(16)-ceramide addiction was revealed, and this was associated with increased tumor growth, whereas downregulation of its synthesis resulted in ER stress-induced apoptosis. By contrast, ceramide synthase 1-generated C(18)-ceramide has been shown to suppress tumor growth in various cancer models, both in situ and in vivo. In addition, ceramide metabolism to generate sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 mediates, with or without the involvement of G-protein-coupled S1P receptor signaling, prosurvival, angiogenesis, metastasis and/or resistance to drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which sphingolipid metabolism and signaling regulate tumor growth and progression, such as identifying direct intracellular protein targets of sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated ceramides by ceramide synthases and/or S1P in the regulation of cancer pathogenesis, as well as the development of sphingolipid-based cancer therapeutics and drug resistance.
鞘脂类已成为生物效应分子，控制着癌症中细胞生长和增殖的各个方面，而癌症已成为全球最致命的疾病。这些脂质分子也与癌症化疗药物的作用机制有关。神经酰胺是鞘脂代谢的中心分子，通常介导抗增殖反应，如细胞生长抑制、细胞凋亡诱导、衰老调节、内质网应激反应和/或自噬。有趣的是，最近的研究表明，从头合成的神经酰胺可能在促进/抑制肿瘤方面具有独特且相反的作用，并且这些活性基于其脂肪酸链长、亚细胞定位和/或直接下游靶标。例如，在头颈部癌细胞中，发现了神经酰胺合酶 6/C(16)-神经酰胺成瘾，这与肿瘤生长增加有关，而其合成的下调则导致内质网应激诱导的细胞凋亡。相比之下，神经酰胺合酶 1 产生的 C(18)-神经酰胺已被证明在各种原位和体内癌症模型中抑制肿瘤生长。此外，鞘氨醇激酶 1 和 2 将鞘脂代谢为神经酰胺-1-磷酸 (S1P)，介导或不涉及 G 蛋白偶联 S1P 受体信号，促进存活、血管生成、转移和/或对药物诱导的细胞凋亡的抵抗。重要的是，最近关于鞘脂代谢和信号调节肿瘤生长和进展的机制的发现，例如确定鞘脂的直接细胞内蛋白靶标，对于开发新的化疗策略至关重要。因此，在本文中，我们将介绍最近的研究结论，这些研究描述了神经酰胺合酶和/或 S1P 从头合成的神经酰胺在调节癌症发病机制中的相反作用，以及基于鞘脂的癌症治疗和药物耐药性的发展。
