Abstract
Sphingolipids are a class of essential lipids implicated in constructing cellular membranes and regulating nearly all cellular functions. Sphingolipid metabolic network is centered with the ceramide–sphingomyelin axis. Ceramide is well-recognized as a pro-apoptotic signal; while sphingomyelin, as the most abundant type of sphingolipids, is required for cell growth. Therefore, the balance between these two sphingolipids can be critical for cancer cell survival and functioning. Ceramide transfer protein (CERT) dictates the ratio of ceramide to sphingomyelin within the cell. It is the only lipid transfer protein that specifically delivers ceramide from the endoplasmic reticulum to the Golgi apparatus, where ceramide serves as the substrate for sphingomyelin synthesis. In the past two decades, an increasing body of evidence has suggested a critical role of CERT in cancer, but much more intensive efforts are required to draw a definite conclusion. Herein, we review all research findings of CERT, focusing on its molecular structure, cellular functions and implications in cancer. This comprehensive review of CERT will help to better understand the molecular mechanism of cancer and inspire to identify novel druggable targets.
Highlights
Cancer cells exhibit altered lipid profile and metabolism, enabling them to meet the bioenergetic, biochemical and biophysical requirements for cancer initiation, progression and metastasis [1,2]
Sphingolipids are a class of critical molecular players in cancer: sphingomyelin, ceramide and glycosphingolipids serve as structural lipids in the cellular membrane, where they form sphingolipid-enriched microdomains and regulate cancer cell signaling [11,12]; while ceramide, sphingosine and sphingosine 1-phosphate (S1P) can directly function as signaling molecules implicated in cancer cell proliferation, metabolism and death, inflammation, tumor angiogenesis, metastasis and drug resistance [13,14,15,16,17,18]
The structure–function relationship underlying the Ceramide transfer protein (CERT)-mediated ceramide transport from the endoplasmic reticulum (ER) to the trans-Golgi has been largely elucidated. This core function of CERT is dependent on its Pleckstrin Homology (PH) domain (Golgi targeting), START domain and FFAT motif (ER targeting), and it is tightly regulated by serial phosphorylation in the serine-rich motif (SRM)
Summary
Cancer cells exhibit altered lipid profile and metabolism, enabling them to meet the bioenergetic, biochemical and biophysical requirements for cancer initiation, progression and metastasis [1,2]. Sphingosine contains 18-carbon (C18) with two hydroxyl groups and one trans-double bond at its C4 position, and it is denoted as 4E-d18:1; while ceramide that possesses a fatty acyl chain in 16-carbon length via the N-link to the sphingoid base is abbreviated as C18:1/C16:0 or C16:0 in short [39]. Ceramide is sitting at the central point of the de novo biosynthetic and catabolic pathways in the sphingolipid metabolic network (Figure 2) It functions as a signaling molecule in most cellular events, while sphingomyelin, generated from ceramide, represents the most abundant sphingolipid subclass in cellular membranes
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