Altered sphingolipid metabolism contributes to cancer progression and presents an exploitable target for the development of novel chemotherapeutics. Bioactive sphingolipid metabolites also have the potential to serve as vital biomarkers for cancer and be utilized to determine disease progression, as well as guide therapeutic regimens. Moreover, identification of these sphingolipid biomarkers is achievable based on recent technological advances in sphingolipidomics, which have aided in detection of sphingolipid metabolites through tools like mass spectrometry. Excellent reviews have previously focused on the biochemical role that sphingolipids have in cancer pathogenesis and treatment. The aim of this review is to concentrate on the critical metabolites and enzymes that contribute to the dysregulation in sphingolipid metabolism, and highlight relevant translational research that is directed towards novel therapies.

The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C₆-ceramide (C₆) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time- and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C₆-ceramide may be a promising therapeutic approach for a fatal leukemia.

IntroductionLarge granular lymphocyte (LGL) leukemia is a lymphoproliferative disease of either CD3 ϩ cytotoxic T lymphocytes (CTLs) or CD3 Ϫ natural killer cells (NK cells). The majority of LGL patients with T-cell (CD3 ϩ , CD8 ϩ /CD57 ϩ ) or NK-cell (CD3 Ϫ , CD16 ϩ / CD56 ϩ ) leukemia have a clinically indolent course. 1,2 LeukemicLGLs of T-cell phenotype reflect polarized expansion of CD8 ϩ terminal-effector memory cells. 3 Expanded NK cells have an activated phenotype with dysregulated NK receptor expression. 4,5 Fas resistance is an important biologic feature in leukemic LGLs of both T-cell and NK-cell type. 3,6 Constitutive activation of survival signaling pathways is a central pathogenetic mechanism in LGL leukemia. Previously, phosphatidylinositol-3 (PI3) kinase activation and signal transducer and activator of transcription 3 upregulation of Mcl-1 were shown to be important for survival of leukemic T-LGLs. [7][8][9] More recently, molecular profiling of T-LGL leukemia revealed a survival role for constitutive sphingolipid signaling. 10 Survival mechanisms in the NK type of LGL leukemia have been less extensively studied; however, a constitutively active retrovirus-associated DNA sequence (RAS)/mitogen-activated protein kinase (MEK)/extracellular signal-related kinase (ERK) survival pathway was identified. 6 Given the complexity and interactive nature of signaling pathways, it is difficult to determine the importance of individual pathway components when studied in isolation. Using a network modeling approach, we found that the presence of interleukin-15 (IL-15) and platelet-derived growth factor (PDGF) is sufficient to reproduce all known deregulations in T-LGL leukemia. 11 Work in this study focused on further examining the pivotal role of PDGF. We found that PDGF mediates survival of leukemic LGLs of both T-and NK-cell origin through an autocrine regulatory pathway. Methods ReagentsAll chemicals were purchased from Sigma-Aldrich unless otherwise specified. Recombinant human (rh) PDGF-BB was purchased from ProSpec-TANY TechnoGene LTD; rhIL-2, from Promega Corporation; and human T-lymphotropic virus-I (HTLV-I)-and HTLV-II-infected plasma, from Zeptometrix. Antibodies and inhibitors were obtained from the following sources and used at the dilutions recommended by the manufacturers: anti-PDGFR-␣ (951) and anti-PDGFR-␤ (958) polyclonal antibodies, anti-phospho-Tyr monoclonal antibody (PY99), goat anti-mouse immunoglobulin G (IgG) antibody (Santa Cruz Biotechnology Inc); anti-PDGF-BB neutralizing antibody and anti-PDGF-BB antibody for immunocytochemistry/immunofluorescence (ICC/IF; Abcam Inc); anti-phospho-AKT and total AKT polyclonal antibodies, anti-MEK1/2, anti-phospho-MEK1/2, anti-ERK1/2, and phospho-ERK1/2 (Cell Signaling Technology); antiphospho-Src (Tyr419) and anti-Src antibodies (Upstate Cell Signaling Solutions); ␤-actin monoclonal antibody (Sigma-Aldrich); mouse antiglyceraldehyde-3-phosphate dehydrogenase (GAPDH) monoclonal antibody (Chemicon International); PI3K inhibitor LY294002 (Cell Signali...