Elevation of Ceramide in Senescence: Role of Sphingolipid Metabolism
Sphingolipids play a wide variety of roles in biological systems. In cancer, the sphingolipids ceramide and sphingosine-1-phosphate play offsetting roles in balancing cell proliferation with senescence and survival with death. By tipping the balance toward more ceramide and less sphingosine-1-phosphate cells are less prone to survive and proliferate. Cellular senescence is thought to have evolved as a mechanism to limit cancer growth. Senescent cells produce higher levels of ceramide and this appears to contribute to this phenotype. Ceramide is at the hub of metabolism of a variety of sphingolipids. Ceramide levels are determined through the balance of a large group of enzymes. In senescence, several of these are modulated in a coordinated fashion such that ceramide levels are kept elevated compared to their proliferative cell counterparts. Ceramide can work through a variety of targets including PKC, PP2A, PP1, phospholipase D, kinase suppressor of Ras and cathepsin D. By blocking the action of the phospholipase D and PKC ceramide can, in part, maintain these cells in a postproliferative state. There are a variety of pharmaceutical tools available to modulate sphingolipid levels in cells through the enzymes that metabolize them. These have proven very promising for potential cancer drugs.
KeywordsCeramide-activated protein kinase Ceramides Dihydroceramide Glucosylceramide synthesis Glycosphingolipids and sphingomyelin Human diploid fibroblasts (HDF) Human umbilical vein endothelial cells (HUVECs) Lipidomics profiles Protein phosphatases Sphingolipid metabolism
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