Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer

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.

Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT

“…One of the most desirable applications of CERT inhibitors may be their therapeutic use in cancer, because the upregulation of intracellular ceramide levels by the blockage of the ceramide-to-sphingomyelin conversion through the use of CERT inhibitors would facilitate the efficacy of existing anti-cancer drugs, as previously proposed [95]. For further possible applications of CERT inhibitors in the treatment of cancer, see the recent review by Chung et al [88].…”

“…The LTP-mediated inter-membrane transfer of a lipid involves at least four biophysical steps [1]: (i) an LTP binds to the donor membrane, (ii) the LTP extracts a lipid from the donor membrane by enclosing the hydrophobic moiety of the lipid in its hydrophobic pocket, (iii) the lipid-holding LTP moves to the acceptor membrane, and (iv) the LTP releases the lipid to the acceptor membrane. Furthermore, after releasing the lipid to the acceptor membrane, some LTPs (e.g., the cholesterol/PtdIns(4)P exchanging-transfer protein OSBP) catalyze the retrograde transport of another specific lipid from the "acceptor membrane" to the "donor membrane", to exchange different lipid types between different organelles [87,88].…”

In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

“…Moreover, COL4A3BP (Ceramide transfer protein or CERT) is a lipid transfer protein that transport ceramide, a pro-apoptotic signal molecule, from the endoplasmic reticulum (ER) to the Golgi apparatus [76], which has been found upregulated in different cancers, such as ovarian cancer [77]. Although COL4A3BP dysregulation has not been previously associated with EC, this protein has been proposed as an interesting therapeutic target for chemotherapy-resistant cancers due to the effect of COL4A3BP downregulation in promoting endoplasmic reticulum stress [77,78].…”

Unraveling the Intricate Link: Deciphering the Role of the Golgi Apparatus in Breast Cancer Progression

“…CERT specializes in carrying ceramide from the ER to the TGN, where it undergoes conversion to sphingomyelin [ 55 ]. Its inhibition or depletion results in ceramide accumulation, catalyzing ceramide-induced ER stress.…”