Neutral Sphingomyelinase 2: Structure, Function, and Regulation with Emphasis on Nitric Oxide Involvement and Potential Implications for Cancer Therapy

Abstract

Mammalian neutral sphingomyelinase 2 is encoded by the gene smpd3 and belongs to the family of hydrolases which catalyze the breakdown of sphingomyelin to form ceramide and phosphocholine. The bioactive ceramide can then act as the second messenger molecule capable of mediating an array of cellular events, such as growth arrest and apoptosis. Recent studies have revealed that the expression and activity of neutral sphingomyelinase 2 are selectively regulated and this regulation can take place at the transcriptional level as well as at the post-translational level. Upon exposure to oxidative stress, endoplasmic reticulum stress, tumour necrosis factor alpha stimulation or anti-cancer drugs, altered neutral sphingomyelinase 2 activity directly translates into changes in ceramide levels which help cells mount an appropriate response. On the other hand, inappropriate activation or inhibition of neutral sphingomyelinase 2 could contribute to the development of pathological conditions such as cancer and endothelial dysfunction. In this chapter, we focus on current knowledge regarding neutral sphingomyelinase 2 structure, the regulation of its activity, its function and potential involvement in stress response and cancer genesis.