Sarah Spiegel

The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer

Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.

Sphingosine-1-Phosphate: Member of a New Class of Lipid Second Messengers

Homeostasis of multicellular organisms as well as their normal development depends on the balance between cellular proliferation, differentiation, and cell death or apoptosis. Ceramide, sphingosine, and sphingosine-1-phosphate (SPP), metabolites of sphingolipids, and ubiquitous components of eukaryotic cell membranes, have recently emerged as members of a new class of signaling molecules regulating these diverse cellular processes.1–4 Sphingolipid metabolism involves removal of their polar headgroups; for example, phosphorylcholine from sphingomyelin by acidic or neutral sphingomyelinases to produce ceramide,5 which can then be cleaved by ceramidases to release fatty acid and the free long-chain base (sphingosine or sphinganine).6 Sphingosine can be phosphorylated to SPP by sphingosine kinase,7 reacylated to ceramide, or methylated.8 SPP in turn can undergo dephosphorylation to sphingosine,9 or cleavage to ethanolamine phosphate and trans-2hexadecenal by a pyridoxal phosphate-dependent lyase.10,11 Although all of these sphingolipid metabolites may play important roles in cell regulation, this review is focused on current knowledge regarding the second messenger role of SPP in regulating the fate of the cell.

New aspects of sphingosine-1-phosphate in inflammation, cancer progression, and metastasis

L acid lipase deficiency (LAL-D) is an inherited and systemic disorder related to impaired cholesterol ester and triglyceride hydroxylation. This condition is related to the occurrence of LIPA gene deleterious mutations and is causative of a storage disease. LAL-D prevalence is very rare, and the clinical onset ranges abroad all ages since infancy to adulthood. The milder clinical picture affects children and adults and is frequently diagnosed based on the liver impairment. The major features are increased transaminase levels and hepatomegaly which variably progresses to liver failure and death. This presentation mimics common disorders including liver steatohepatits or primary hyperlipidemia then it should be underdiagnosed. Serum total (TC) and LDL cholesterol (LDL-C) increases are additional frequent markers while HDL-C is commonly reduced. This latter profile is pro-atherogenic but pathogenetic mechanisms are still discussed and poorly evaluated. Great progress has been reached since the screening test and the enzyme replacement therapy availability. The screening test is not considered to be applied to the general population but a specific clinical-biochemical marker to ascertain subjects to submit to LALD screening test still lacks. A diagnostic algorithm based on a 3 steps levels were applied to primary affected hypercholesterolemic pediatric subjects. 811 outpatients 5-18 yrs old were included in the study. A selection from the database of subjects to submit to the dried blood screening test for LALD detection was: LDL-C levels above160mg/dl, Recessive pedigree and; Transaminase analysis exceeding normal lab reference value. Molecular analysis of LIPA gene completed the analysis. Results of this study are represented by 4 new diagnosis 3/4 including asymptomatic children 3-5 yrs old. In conclusion lipid profile is required in pediatrics and attention should be paid also to recessive disorders, when changes are confirmed, to reach a final diagnosis and to improve the patient outcome. Lipids should represent a very precocious diagnostic marker of LAL-D affected children.Statement of the Problem: Immune-suppressive agents such as methylprednisolone and cyclosporine exert tremendous side effects, because of high dosage and long-term application required for immune suppression after organ transplantation. Major side effects of methylprednisolone include bleeding of the GI tract, hypertension, and osteoporosis, whereas cyclosporine is nephrotoxic. Liposomes are phospholipid particles that allow delivery of drugs preferentially to the reticuloendothelial system (RES). Liposomes as vehicles for drug delivery can be applied both systematically and topically.Statement of the Problem: Membrane fatty acids contribute to several aspects of cellular homeostasis, growth and signaling. Membrane lipidomics, which follows up the remodeling and modifications of the fatty acid content, is the basic analytical tool for obtaining molecular profiles of human subjects under health and disease conditions. Nowadays, it is used as diagnostic tool for personalized nutra-strategies and nutrilipidomics approach. Tissue specific fatty acid analysis is a difficult strategy, mainly due to its invasive character. Thus, mature erythrocytes, which are circulating for 3-4 months around the body, represent a suitable sample for membrane fatty acid-based lipidomics.

Sphingolipid Metabolites in Signal Transduction

The importance of intracellular signaling molecules derived from sphingolipids, a major class of membrane lipids, has only recently begun to be appreciated. Sphingolipids contain a long-chain sphingoid base backbone, of which sphingosine is the most common; an amide-linked fatty acid; and a polar head group (hydroxyl for ceramide, phosphorylcholine for sphingomyelin, and carbohydrate residues of varying complexity for glycosphingolipids). Biological activity is exhibited not only by the more complex species of sphingolipids, but also by their metabolic products, with such metabolites as ceramide, sphingosine, and sphingosine 1-phosphate (SPP) emerging as a distinct class of lipid second messengers (1–5).