Bioactive sphingolipids in inflammation and cancer

Abstract

The bioactive sphingolipids ceramide, sphingosine, and sphingosine‐1‐phosphate (S1P) have recently emerged as important modulators of cell growth, cellular senescence, and programmed cell death. In order to study the roles of these lipids in cell regulation, it is important to understand their interconnected metabolic pathways. Ceramide, the backbone of sphingolipids is broken down by one of many ceramidases (CDAse) to generate sphingosine the precursor of S1P by the action of sphingosine kinase (SK). The enzymes involved in the breakdown of ceramide, and in the generation and breakdown of S1P all appear to be important regulated enzymes. Our laboratory has focused on studying the role of CDAse, SK, and its product S1P in inflammation and in cancer. We have recently implicated the SK1/ S1P pathway in mediating inflammatory responses in cells and most recently in vivo in a DSS model of colitis. In order to determine the mechanism of substrate generation for SK in inflammation we are utilizing a combination of CDAse inhibitors and KO mice. We demonstrate distinct roles for neutral and acid CDAses in regulation of ceramide/ S1P levels in the stromal and epithelial layers of intestine and consequently in the inflammatory response to DSS‐induced colitis. In addition, significant evidence has implicated bioactive sphingolipids in cancer progression and apoptosis. In probing the role of CDAses and SK in cancer we find distinct roles for the different CDAses and SK1 in colon cancer progression. These studies lend strong support for the role of bioactive lipids and their metabolizing enzymes in inflammation and cancer and make them attractive therapeutic targets for inflammation and cancer.