Abstract
Inflammation is part of our body's response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.
Highlights
Sphingolipids and their derivatives are important structural components of mammalian cell membranes
In agreement with previous reports [61] along with our recent study [62], it was suggested that knockdown of SphK2 with siRNA or inhibition of SphK2 activity with the selective pharmacological drugs reduces cancer cell growth, migration, and invasion [61,62,63,64,65,66,67,68], induces apoptosis by accumulating proapoptotic ceramides [63, 64, 69, 70], and promotes proteasomal inhibitor-mediated endoplasmic reticulum (ER) stress resulting in myeloma cell death [71, 72]
The findings suggest that SphK1 and S1P lyases are potential therapeutic targets for hepatocellular carcinoma (HCC) treatment
Summary
Sphingolipids and their derivatives are important structural components of mammalian cell membranes. In response to local tissue damage or infection, neutrophils, macrophages, and other immune cells are recruited to the inflamed tissue from the circulation where they are involved in assisting resolution of inflammation. These processes are marked by the synthesis and secretion of cytokines, chemokines, extracellular matrix proteins, and various lipid mediators including sphingolipid metabolites. We found that high expression of ORMDL3 in lung epithelial cells and macrophages enhances ceramide production, which promoted chronic inflammation, airway hyper responsiveness, and mucus production during house dust mite-induced allergic asthma in a mouse model [16]. This review focuses on the current understanding of the role of S1P and C1P in inflammation and cancer
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