卷 11, 编号 9 (2011)

Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions including the promotion of cell survival, proliferation and migration, as well as the regulation of angiogenesis, inflammation, immunity, vascular permeability and nuclear mechanisms that control gene transcription. S1P is derived from metabolism of ceramide, which itself has diverse and generally growth-inhibitory effects through its impact on downstream targets involved in regulation of apoptosis, senescence and cell cycle progression. Regulation of ceramide, S1P and the biochemical steps that modulate the balance and interconversion of these two lipids are major determinants of cell fate, a concept referred to as the “sphingolipid rheostat.” There is abundant evidence that the sphingolipid rheostat plays a role in the origination, progression and drug resistance patterns of hematopoietic malignancies. The pathway has also been exploited to circumvent the problem of chemotherapy resistance in leukemia and lymphoma. Given the broad effects of sphingolipids, targeting multiple steps in the metabolic pathway may provide possible therapeutic avenues. However, new observations have revealed that sphingolipid signaling effects are more complex than previously recognized, requiring a revision of the sphingolipid rheostat model. Here, we summarize recent insights regarding the sphingolipid metabolic pathway and its role in hematopoietic malignancies.

The sphingolipids ceramide, sphingosine and sphingosine 1-phosphate have emerged as important signaling molecules that regulate a number of important cellular processes. Sphingosine 1-phosphate enhances cell survival and proliferation, and also regulates angiogenesis, cell invasion, and differentiation via both its cell surface G protein-coupled receptors and recently identified intracellular effectors. In contrast, ceramide and sphingosine elicit growth arrest and apoptosis through direct modulation of a number of intracellular targets. The cellular balance of these sphingolipids contributes to the determination of cell fate, and it is now clear that disruption in this 'sphingolipid rheostat' contributes to the development, progression and chemotherapeutic resistance of both hematological malignancies and solid tumors. The sphingosine kinases are central regulators of this pathway since they not only increase sphingosine 1-phosphate and assist in reduction of ceramide and sphingosine, but are also regulated at multiple levels by external stimuli. Thus, targeting the regulation of the sphingosine kinases may be a viable therapeutic strategy for a diverse array of cancers. Here, we describe the current knowledge of sphingosine kinase regulation, effects of current and potential chemotherapeutic agents on this system, and discuss the implications of this for the treatment of hematological malignancies and other cancers.

The sphingolipid sphingosine-1-phosphate (S1P) is an important regulator of immune cell functions in vivo. Besides recruiting lymphocytes to blood and lymph, it may promote immune cell survival and proliferation, but also interferes with their activation. Hereby, S1P may act as an intracellular second messenger or cofactor or, upon being secreted from cells, may bind to and activate a family of specific G-protein-coupled receptors (S1PR1-5). Extracellular versus intracellular S1P hereby might trigger synergistic/identical or fundamentally distinct responses. Furthermore, engagement of different S1PRs is connected to different functional outcome. This complexity is exemplified by the influence of S1P on the inflammatory potential of macrophages, shaping their role in inflammatory pathologies such as atherosclerosis and cancer. Here, we summarize the recent progress in understanding the impact of S1P signaling in macrophage biology, discuss its impact in solid as well as 'wet' tumors and elaborate potential options to interfere with S1P signaling in the context of cancer.

Autophagy is an evolutionary conserved process by which cells recycle intracellular materials to maintain homeostasis in different cellular contexts. Under basal conditions it prevents accumulation of damaged proteins and organelles; during starvation, autophagy provides cells with sufficient nutrients to survive. Sphingolipids are a family of bioactive molecules modulating vital cellular functions such as apoptosis, cell cycle arrest or proliferation. Besides these functions, some sphingolipids like ceramide, sphingosine- 1-phosphate or gangliosides have been described to promote autophagy in several cancer cell lines. Current evidence supports the notion that induction of autophagic cell death can halt tumorigenesis. Of interest, some chemotherapeutic agents used for the treatment of hematological malignancies trigger the production of endogenous sphingolipids with pro-autophagic effects. In this review we describe the regulation and functions of the sphingolipid-induced autophagy and the tight relationship with the cancer cell response to current chemotherapeutic regimens.

Since the discovery and initial characterizations of sphingolipids (SLs) in 1884, extensive research has established that these molecules not only are structural components of eukaryotic membranes but they are also critical bioactive lipids involved in fundamental cellular processes such as proliferation, differentiation, apoptosis, inflammation, migration, and autophagy. Altered SL metabolism has been observed in many pathological conditions including hematological malignancies. Thus, targeting the SL pathway to induce lipid changes to counteract specific pathologies is currently being pursued as a promising, novel therapeutic intervention. In this review, we discuss the general characteristics of the SL pathway, illustrating those features relevant to the understanding of the role of SLs in leukemia, and we address novel SL-targeting therapeutic approaches.

Drug resistance represents a serious barrier to the successful treatment of hematological malignancies. In leukemias, resistance mechanisms that involve membrane-resident proteins belonging to the ABC (ATP-binding cassette) transporter protein family are of particular interest, wherein enhanced expression is often associated with poor prognosis and frequent in relapsed or refractory disease. These proteins reduce the intracellular concentration of antitumor agents, greatly diminishing clinical efficacy. Research in this area has been directed at the design of agents, “pump antagonists”, to overcome the effluxing capacity of drug transporters; however, this direction has had limited clinical success. An allied function of ABC transporters like P-glycoprotein (P-gp) is glycolipid trafficking, an area that has not been explored from a therapeutic standpoint. In this capacity, it turns out that glycolipid synthesis can be attenuated by pump antagonists; this is perhaps an adventitious property of P-gp. Recent research in the area of lipid metabolism, specifically ceramide and glycolipids, has provided insight into the function of glycosphingolipids in multidrug resistance and in the action of chemotherapy. This review is intended to bring together those aspects of glycosphingolipid metabolism that might be leveraged to enhance the therapeutic performance of ceramide and to discuss how ABC transporters like P-gp might be targeted to potentiate and magnify ceramide-driven proapoptotic cascades.

The bioactive sphingolipid, ceramide, has garnered major interest as a principle regulator of cellular stress, proliferation, senescence, and death. Of particular interest to cancer biologists and clinical oncologist, dysregulated ceramide metabolism has been documented in both solid and non-solid malignancies. Moreover, most anticancer chemotherapeutics stimulate ceramide accumulation through increased ceramide synthesis or through the inhibition of ceramide catabolism. In fact, neutralization of ceramide via glycosylation or phosphorylation in malignant cells has been linked to multidrug chemoresistance. New therapeutic strategies to overcome chemoresistance focus on increasing endogenous ceramide levels by stimulating ceramide synthesis, by inhibiting ceramide neutralization, or by the direct delivery of exogenous ceramide. This review will discuss new therapeutic strategies designed specifically to modulate ceramide metabolism, as well as nanoscale delivery systems engineered to selectively deliver ceramide to cancerous cells and tissues.