Ruvolo Peter P
Institute of Molecular Medicine, University of Texas Health Science Center, IBT-900, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.
Pharmacol Res. 2003 May;47(5):383-92. doi: 10.1016/s1043-6618(03)00050-1.
The sphingolipid ceramide has proven to be a powerful second-signal effector molecule that regulates diverse cellular processes including apoptosis, cell senescence, the cell cycle, and cellular differentiation. Ceramide has been shown to activate a number of enzymes involved in stress signaling cascades including both protein kinases and protein phosphatases. Ceramide kinase targets include stress-activated protein kinases (SAPKs) such as the jun kinases (JNKs), kinase suppressor of Ras (KSR), and the atypical protein kinase C (PKC) isoform, PKC zeta. Ceramide also is capable of activating protein phosphatases such as protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). It is through these protein phosphatases that ceramide can indirectly inhibit kinases that are key components of pro-growth signaling processes such as the classical and novel PKC isoforms and protein kinase B (PKB; also known as Akt). However, the mechanisms how ceramide directly activates enzymes such as JNK and PP2A are still not clear. Elucidation of these mechanisms will reveal how ceramide functions in stress signaling cascades and will provide important information on cellular processes such as apoptosis. It is becoming clear that the ceramide generation is a near universal feature of programmed cell death. It is possible that during at least some apoptotic events, ceramide may be required to activate stress-signal cascades that lead to cell death, while concurrently, suppressing growth and survival pathways in the dying cell. Such a versatile role for ceramide is not unreasonable since ceramide has been implicated as having a role in both intrinsic (i.e. mitochondrial) and extrinsic (i.e. death receptor-mediated) apoptotic pathways. The recent data suggesting that aberrant glycosylation of ceramide (i.e. inactivation of the molecule) may be an important cause of drug resistance in certain cancers suggests that ceramide-mediated signaling cascades are critical components of chemotherapy-induced cell killing. Taken together, these properties of ceramide suggest that this important second-signal molecule may be an important target in anti-neoplastic strategies.
鞘脂神经酰胺已被证明是一种强大的第二信号效应分子，可调节多种细胞过程，包括细胞凋亡、细胞衰老、细胞周期和细胞分化。神经酰胺已被证明能激活许多参与应激信号级联反应的酶，包括蛋白激酶和蛋白磷酸酶。神经酰胺激酶的作用靶点包括应激激活蛋白激酶（SAPK），如Jun激酶（JNK）、Ras激酶抑制因子（KSR）以及非典型蛋白激酶C（PKC）亚型PKCζ。神经酰胺还能够激活蛋白磷酸酶，如蛋白磷酸酶1（PP1）和蛋白磷酸酶2A（PP2A）。正是通过这些蛋白磷酸酶，神经酰胺能够间接抑制激酶，这些激酶是促生长信号过程（如经典和新型PKC亚型以及蛋白激酶B（PKB；也称为Akt））的关键组成部分。然而，神经酰胺如何直接激活JNK和PP2A等酶的机制仍不清楚。阐明这些机制将揭示神经酰胺在应激信号级联反应中的作用方式，并将提供有关细胞凋亡等细胞过程的重要信息。越来越明显的是，神经酰胺的生成是程序性细胞死亡的一个几乎普遍的特征。在至少一些凋亡事件中，神经酰胺可能需要激活导致细胞死亡的应激信号级联反应，同时抑制垂死细胞中的生长和存活途径。神经酰胺的这种多功能作用并非不合理，因为神经酰胺已被认为在内在（即线粒体）和外在（即死亡受体介导）凋亡途径中均起作用。最近的数据表明，神经酰胺的异常糖基化（即分子失活）可能是某些癌症耐药性的一个重要原因，这表明神经酰胺介导的信号级联反应是化疗诱导细胞杀伤的关键组成部分。综上所述，神经酰胺的这些特性表明，这种重要的第二信号分子可能是抗肿瘤策略中的一个重要靶点。
