Abstract
Sphingolipids are both structural molecules that are essential for cell architecture and second messengers that are involved in numerous cell functions. Ceramide is the central hub of sphingolipid metabolism. In addition to being the precursor of complex sphingolipids, ceramides induce cell cycle arrest and promote cell death and inflammation. At least some of the enzymes involved in the regulation of sphingolipid metabolism are altered in carcinogenesis, and some are targets for anticancer drugs. A number of scientific reports have shown how alterations in sphingolipid pools can affect cell proliferation, survival and migration. Determination of sphingolipid levels and the regulation of the enzymes that are implicated in their metabolism is a key factor for developing novel therapeutic strategies or improving conventional therapies. The present review highlights the importance of bioactive sphingolipids and their regulatory enzymes as targets for therapeutic interventions with especial emphasis in carcinogenesis and cancer dissemination.
Highlights
Sphingolipids are fundamental components of cell membranes
Thudichum in 1876 and were considered merely as structural molecules of cell architecture. It was not until 1986 when Hannun and co-workers demonstrated that some sphingolipids were bioactive molecules, showing that sphingosine was capable of inhibiting protein kinase C (PKC) [1]
This study has shown that drugs such as Lomitapide, Clevidipine, Fluralaner and Eltrombopag inhibit ceramide transfer protein (CERT) in HeLa cells [242]
Summary
Sphingolipids are fundamental components of cell membranes. They were discovered in brain extracts by J. The fatty acid desaturase family protein FADS3 has recently been described as a ceramide desaturase that adds a double bond at the Δ14Z position [34,35] This enzyme could be of great importance in diseases related to the functional loss of Des. CerS is a family of six different isoforms, each of which synthesizes ceramides with different chain lengths of fatty acyl-CoA, resulting in a specific activity This fact is important, since, for example, CerS1 generates 18-carbon Cer (C18:0-Ceramide) that inhibits tumor growth [73], whereas CerS5/6 produces C16:0-Ceramide, an anti-apoptotic metabolite in human head and neck squamous cell carcinomas [74] that is involved in type II diabetes [17,33,75] and that has proinflammatory properties [76]. It was observed that its inhibition with specific siRNAs produced a lysosomal dysfunction that, together with anticancer treatment, caused cell death [134]
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