Editorial [Hot Topic: Therapeutic Targeting of the Sphingolipid “Biostat” in Hematologic Malignancies (Guest Editors: Thomas P. Loughran and Hong-Gang Wang)]

Although sphingolipids were originally discovered in brain extracts more than one and a quarter centuries ago, our understanding of their roles in physiological and pathophysiological processes only began in the last three decades. Sphingolipids are a diverse group of lipids in which fatty acids are linked via amide bonds to a long-chain base or sphingoid (e.g., sphingosine). The term “sphingo-” was coined by the German biochemist Johann Ludwig Wilhelm Thudichum in 1884 after the Greek mythological creature Sphinx because of its enigmatic nature. Initially considered to be simply the building blocks of biomembranes, the discovery that sphingosine inhibits protein kinase C and induces apoptosis by Yusuf Hannun and colleagues in 1986 has fueled a tremendous increase in research on the roles that sphingolipids play in regulating various cellular functions including cell proliferation, differentiation, apoptosis, cell survival and death, autophagy, and immune response. Accordingly, our knowledge regarding the connections between sphingolipids and human pathophysiology has continued to expand. It is now apparent that dysfunctional sphingolipid metabolism is associated with multiple types of cancer including leukemias. Individual sphingolipid metabolites that correlate with oncogenesis, transformation and metastasis have been identified. There is increasing evidence that an imbalance in the “sphingolipid rheostat” contributes to the pathogenesis and drug resistance of hematological malignancies. In this special series, therefore, we have collected a comprehensive set of reviews on the roles of bioactive sphingolipid metabolites in cancer biology and therapeutics. As will become evident from the superb reviews in this series, the biosynthesis and metabolism of sphingolipids are much more complex and involve a large number of intermediate metabolites. Different sphingolipid species can have distinct biological activities. For example, while sphingosine-1-phosphate (S1P), a phosphorylated product of sphingosine catalyzed by sphingosine kinases, promotes cell growth and survival, its precursors, sphingosine and ceramide, play a role in growth arrest and cell death. Since these metabolites are interconvertible, it has been proposed by Sarah Spiegel and colleagues that it is not their absolute amounts, but rather the balance between these counter-acting sphingolipid metabolites, that controls the cell fate decision. To best appreciate the “sphingolipid rheostat” model, we begin this series with a historical perspective and overview of sphingolipid signaling pathways and its roles in hematopoietic malignancies by Loh et al. The regulation and mechanisms of action of S1P and the kinases responsible for its production in hematological malignancies are thoroughly reviewed by Stevenson et al and Pitson et al. S1P is generated from sphingosine by sphingosine kinases (SphK1 and SphK2). In addition to its intracellular roles in NF-κB activation and epigenetic regulation of gene expression, S1P can be exported outside the cell by ATP-binding cassette transporters, where it signals through five S1P specific G protein-coupled receptors to exert its effects on cancer progression including cell growth, survival, migration, and angiogenesis. A more specific characterization of S1P receptors (S1PRs) and their roles in cancer development is presented in the review by Watters et al. Interestingly, sphingosine kinases and its product S1P also have important roles in regulation of macrophage activation and inflammatory responses, as described by Weigert et al. Moreover, recent findings suggest that the SphK1/S1P signaling regulates the hypoxic response of tumor cells, as reviewed by Cuvillier and Ader. In particular, these reviews also evaluate the potential of pharmacological agents that modulate the SphK/S1P/S1PRs signaling pathway for the treatment of hematological cancers. Sphingolipid metabolism is highly orchestrated by numerous enzymes whose activities are dependent on many factors including intracellular location. Ceramidases are key enzymes that regulate cellular levels of ceramide and sphingosine by catalyzing the cleavage of ceramide into sphingosine and fatty acids. The key roles of ceramidases, particularly acid ceramidase, in cancer initiation, progression and response to radio- and chemotherapy are reviewed by Fabrias et al. Accumulating evidence suggests that inhibition of acid ceramidase may enhance the efficacy of chemotherapeutic drugs in cancer patients. Interestingly, recent studies have revealed a role for sphingolipid metabolites in the regulation of autophagy, a lysosomal catabolic pathway. Autophagy plays vital roles in the quality control of cellular components and cell survival by eliminating damaged materials and supplying nutrients. In this issue, Bedia et al. describe the regulation of autophagy by sphingolipids and its contribution to the response of cancer cells to chemotherapy. With the explosion of information on sphingolipid metabolites in recent years, this is an opportune time to speed efforts to translate our current knowledge about sphingolipid signaling into better cancer prevention and treatment, as discussed by Burns and Luberto. Drug resistance is a major obstacle for the successful treatment of cancer. Accumulating evidence suggests that sphingolipids play an important role in the regulation of multidrug resistance and the action of chemotherapeutic drugs, as reviewed by Spassieva and Bieberich as well as Gouaze-Andersson and Cabot. Ceramide is a central metabolite of the sphingolipid pathway that plays a critical role in cancer cell death induced by chemotherapeutic drugs. Dysregulation of ceramide metabolism is associated with not only malignancy but also multidrug resistance. Indeed, it has recently been shown that CERT, a major regulator of ceramide flux, is increased in drug resistant cancer cells and that suppression of CERT sensitizes cancer cells to anticancer drugs, as reviewed by Scheffer et al. Thus, increasing cellular levels of ceramide by modulating ceramide metabolism or delivering exogenous ceramide (e.g. C6-ceramide) directly into cancer cells has the potential to be a promising therapeutic strategy to overcome multidrug resistance in cancers including hematopoietic malignancies, as discussed by Barth et al.....