Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

Abstract

Sphingolipids are bioactive lipids that participate in a wide variety of biological mechanisms, including cell death and proliferation. The myriad of pro-death and pro-survival cellular pathways involving sphingolipids provide a plethora of opportunities for dysregulation in cancers. In recent years, modulation of these sphingolipid metabolic pathways has been in the forefront of drug discovery for cancer therapeutics. About two decades ago, researchers first showed that standard of care treatments, e.g., chemotherapeutics and radiation, modulate sphingolipid metabolism to increase endogenous ceramides, which kill cancer cells. Strikingly, resistance to these treatments has also been linked to altered sphingolipid metabolism, favoring lipid species that ultimately lead to cell survival. To this end, many inhibitors of sphingolipid metabolism have been developed to further define not only our understanding of these pathways but also to potentially serve as therapeutic interventions. Therefore, understanding how to better use these new drugs that target sphingolipid metabolism, either alone or in combination with current cancer treatments, holds great potential for cancer control. While sphingolipids in cancer have been reviewed previously (Hannun & Obeid, 2018; Lee & Kolesnick, 2017; Morad & Cabot, 2013; Newton, Lima, Maceyka, & Spiegel, 2015; Ogretmen, 2018; Ryland, Fox, Liu, Loughran, & Kester, 2011) in this chapter, we present a comprehensive review on how standard of care therapeutics affects sphingolipid metabolism, the current landscape of sphingolipid inhibitors, and the clinical utility of sphingolipid-based cancer therapeutics.

Glucosylceramide synthase maintains influenza virus entry and infection

“…We hypothesize that because ceramide is a pro-apoptotic molecule [26], cells limit any build-up of this bioactive lipid by converting it to either sphingomyelin or sphingosine/S1P. In HEK 293 UGCG KO cells sphingomyelin levels are comparable to those in WT cells, but sphingosine-1-phosphate levels increase 14-fold, indicating that blocking GlcCer production by removing UGCG may shunt sphingolipid production to sphingosine-1-phosphate.…”

“…Sphingolipid metabolism involves numerous enzymes and intermediary lipids, which predominantly shuttle through ceramide as a main hub [26] (Fig 1). Upon addition of a glucose molecule by glucosylceramide synthase (UGCG), ceramide is converted into the glycosphingolipid glucosylceramide (GlcCer), a pro-survival signaling molecule and a precursor lipid for higher order gangliosides [27].…”

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

“…S1P is linked to increased cellular proliferation, angiogenesis, and motility [ 10 , 16 , 17 , 18 ]. The levels of ceramides and S1P can be modulated based on cellular stress through pathways described as a series of “drains” and “faucets” [ 19 ]. This has led to the concept of the sphingolipid rheostat, which illustrates the consequence of shifting the balance between ceramide (pro-apoptotic) and S1P (pro-proliferative) on cell survival [ 20 , 21 ].…”

Lipid Players of Cellular Senescence

“…These key roles require tight control of lipid biosynthesis and metabolism in order to maintain cellular homeostasis [ 16 , 24 ]. As such, dysregulation of enzymes involved in lipid metabolism has been linked to various diseases, including cancer [ 25 ], neurogenerative diseases [ 16 ], and aging [ 26 ]. Lipid processing enzymes are ideal targets for small-molecule perturbations with potential application in developing novel, lipid-based therapeutic approaches.…”