Thioglycosides Are Efficient Metabolic Decoys of Glycosylation that Reduce Selectin Dependent Leukocyte Adhesion

© 2018 Elsevier Ltd Small-molecule inhibitors of glycosylation can be applied in basic science studies, and clinical investigations as anti-inflammatory, anti-metastatic, and anti-viral therapies. This article demonstrates that thioglycosides represent a class of potent metabolic decoys that resist hydrolysis, and block E-selectin-dependent leukocyte adhesion in models of inflammation

Emerging Roles of Ceramides in Breast Cancer Biology and Therapy

One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy

Specific Triacylglycerols Accumulate <i>via</i> Increased Lipogenesis During 5‑FU-Induced Apoptosis

Lipids are emerging as key regulators of fundamental cellular processes including cell survival, division, and death. Apoptosis, a form of programmed cell death, is accompanied by numerous membrane-related phenotypic changes. However, we have an incomplete understanding of the involvement of specific lipid structures during this process. Here, we report that triacylglycerols are regulated at the molecular level during 5-fluorouracil-induced apoptosis in HCT-116. Mass-spectrometry-based global lipid profiling shows that specific triacylglycerols accumulate during apoptosis. Expression levels and activities of enzymes that are responsible for the biosynthesis and metabolic processing of triacylglycerols suggest that triacylglycerol biosynthesis is responsible for these accumulations. Based on our data, we propose that regulation of triacylglycerols at the molecular level happens downstream of p53 activation and potentially is a mechanism to prevent lipid oxidation during apoptosis

A Protective Role for Triacylglycerols during Apoptosis

Triacylglycerols (TAGs) are one of the major constituents of the glycerolipid family. Their main role in cells is to store excess fatty acids, and they are mostly found within lipid droplets. TAGs contain acyl chains that vary in length and degree of unsaturation, resulting in hundreds of chemically distinct species. We have previously reported that TAGs containing polyunsaturated fatty acyl chains (PUFA-TAGs) accumulate via activation of diacylglycerol acyltransferases during apoptosis. In this work, we show that accumulation of PUFA-TAGs is a general phenomenon during this process. We further show that the accumulated PUFA-TAGs are stored in lipid droplets. Because membrane-residing PUFA phospholipids can undergo oxidation and form reactive species under increased levels of oxidative stress, we hypothesized that incorporation of PUFAs into PUFA-TAGs and their localization within lipid droplets during apoptosis limit the toxicity during this process. Indeed, exogenous delivery of a polyunsaturated fatty acid resulted in a profound accumulation of PUFA phospholipids and rendered cells more sensitive to oxidative stress, causing reduced viability. Overall, our results support the concept that activation of TAG biosynthesis protects cells from lipid peroxide-induced membrane damage under increased levels of oxidative stress during apoptosis. As such, targeting triacylglycerol biosynthesis in cancer cells might represent a new approach to promoting cell death during apoptosis

Dividing cells regulate their lipid composition and localization

SummaryAlthough massive membrane rearrangements occur during cell division, little is known about specific roles that lipids might play in this process. We report that the lipidome changes with the cell cycle. LC-MS-based lipid profiling shows that 11 lipids with specific chemical structures accumulate in dividing cells. Using AFM, we demonstrate differences in the mechanical properties of live dividing cells and their isolated lipids relative to nondividing cells. In parallel, systematic RNAi knockdown of lipid biosynthetic enzymes identified enzymes required for division, which highly correlated with lipids accumulated in dividing cells. We show that cells specifically regulate the localization of lipids to midbodies, membrane-based structures where cleavage occurs. We conclude that cells actively regulate and modulate their lipid composition and localization during division, with both signaling and structural roles likely. This work has broader implications for the active and sustained participation of lipids in basic biology

Membrane Disruption by Very Long Chain Fatty Acids During Necroptosis

In this work we investigate the mechanisms by which very long chain fatty acids (VLCFA) contribute to membrane permeabilization during necroptosis, a form of highly regulated necrotic cell death. We show that inactivating fatty acid elongase ELOVL7 prevents VLCFA accumulation and necroptotic cell death, while it\u27s overexpression causes membrane permeabilization. We show that VLCFA can directly permeabilize lipid bilayers and investigate the basis of these effects by molecular dynamics simulations. Finally, we show that VLCFA can be used as substrates for protein fatty acylation during necroptosis, suggesting another potential mechanism by which VLCFA may mediate membrane permeabilization

Protein Acylation by Saturated Very Long Chain Fatty Acids and Endocytosis Are Involved in Necroptosis

Necroptosis is a form of regulated cell death that is characterized by membrane permeabilization. This permeabilization is responsible for the inflammatory properties of necroptosis and is critical for disease states involving this process. We previously showed that very long chain fatty acids (VLCFAs) are functionally involved in necroptosis, potentially through protein fatty acylation. Here, we define the scope of protein acylation by saturated VLCFAs during necroptosis. We show that mixed lineage kinase like protein (MLKL) and phosphoMLKL, key proteins for membrane permeabilization, are exclusively acylated during necroptosis. Reducing the levels of VLCFAs decreases their membrane recruitment, suggesting that acylation by VLCFAs contributes to their membrane localization. Acylation of phosphoMLKL occurs downstream of phosphorylation and oligomerization and appears to be, in part, mediated by ZDHHC5 (a palmitoyl transferase). We also show that disruption of the clathrin-mediated endocytosis increases cell viability during necroptosis, likely by removing phosphoMLKL from the plasma membrane. </p