The Role of Sphingolipids Metabolism in Cancer Drug Resistance

Abstract

Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer therapy, this review focuses on the main enzymes implicated in sphingolipids metabolism and their intermediate metabolites involved in cancer drug resistance.

It Takes More than Two to Tango: Complex, Hierarchal, and Membrane-Modulated Interactions in the Regulation of Receptor Tyrosine Kinases

“…While the highly hydrophobic ceramides can also affect proteins through direct binding, such as in ceramide-activated Ser–Thr phosphatases (CAPPs) PP1 and PP2A or lysosomal cathepsin D, they can form ceramide platforms, very rigid membrane microdomains recruiting signaling molecules to initiate pathways leading to apoptosis, necroptosis, or lethal mitophagy—an antitumorigenic macroautophagy mechanism resulting in degradation of mitochondria and eventual cell death. Consequently, ceramide levels are commonly decreased in cancer cells, often due to changes in the expression levels of ceramide synthase enzymes generating ceramides of different lengths [ 228 , 229 , 230 ].…”

Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets

“…Sphingolipids have been reported to play a role in the development of drug resistance and radio-resistance in several solid tumor cancer types as well as in chronic lymphocytic leukemia (CLL) ( 196 ). This can arise both through altered sphingolipid metabolism within the cancer cells as well as from changes within microenvironmental cells that then secrete an altered bioactive lipid profile.…”

“…Besides depleting the pro-apoptotic ceramide, the complex glycosphingolipids cluster into plasma and subcellular organelle membrane microdomains and can enhance signal transduction to promote cell proliferation and survival. Overexpression of the GCS enzyme has also been linked to increased expression of the ABCB1 lipid transporter protein (also called P-glycoprotein and encoded by the MDR1 gene) in several cancer cell types, which leads to increased anticancer drug efflux and multidrug resistance ( 196 ). All these properties would increase resistance to multiple anti-cancer drugs via different pathways that converge on GCS.…”

“…However, the S1PR inhibitor FTY720 decreased ABCB1 expression, thereby potentially decreasing the possibility for drug resistance even as it induced apoptosis and autophagy in the cells. The response of MM cells to immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide do not appear to be much affected by changes in ABCB1, although pomalidomide may be a ABCB1 substrate ( 196 ). There is controversy about whether bortezomib is a ABCB1 substrate, but carfilzomib is, and therefore MM cells with increased ABCB1 are more carfilzomib resistant.…”

Art2 mediates selective endocytosis of methionine transporters during adaptation to sphingolipid depletion

“…In yeast, sphingolipids at the PM regulate the activation of TORC2 [5]. Indeed, the variety of regulatory functions served by SLs is underscored by their important role in processes that range from memory and cognition [6] to the progression of cancer [7, 8].…”