Abstract
Ceramide synthase 1 (CERS1) is the most highly expressed CERS in the central nervous system, and ceramide with an 18-carbon–containing fatty acid chain (C18-ceramide) in the brain plays important roles in signaling and sphingolipid development. However, the roles of CERS1 and C18-ceramide in glioma are largely unknown. In the present study, measured by electrospray ionization linear ion trap mass spectrometry, C18-ceramide was significantly lower in glioma tumor tissues compared with controls (P < 0.001), indicating that C18-ceramide might have a role in glioma. These roles were examined by reconstitution of C18-ceramide in U251 and A172 glioma cells via addition of exogenous C18-ceramide or overexpression of CERS1, which has been shown to specifically induce the generation of C18-ceramide. Overexpression of CERS1 or adding exogenous C18-ceramide inhibited cell viability and induced cell death by activating endoplasmic reticulum stress, which induced lethal autophagy and inhibited PI3K/AKT signal pathway in U251 and A172 glioma cells. Moreover, overexpression of CERS1 or adding exogenous C18-ceramide increased the sensitivity of U251 and A172 glioma cells to teniposide (VM-26). Thus, the combined therapy of CERS1/C18-ceramide and VM-26 may be a novel therapeutic strategy for the treatment of human glioma.
Highlights
Gliomas are a group of heterogeneous primary tumors in the central nervous system (CNS)
The C16-ceramide was increased in glioma, and the sphingosine was decreased in glioma
Further data showed that increased generation of C18-ceramide via overexpression of Ceramide synthase 1 (CERS1) or adding exogenous of C18-ceramide resulted in the inhibition of cell viability, which involved the activation of Endoplasmic reticulum (ER) stress, induction of autophagy, and modulation of www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget the PI3K/AKT pathway in glioma cells
Summary
Gliomas are a group of heterogeneous primary tumors in the central nervous system (CNS). Malignant gliomas are the most common primary brain tumors in the CNS and account for approximately 79% of malignant CNS tumors [1]. A hydrophobic backbone of sphingolipids, contains two hydrophobic chains, a long-chain base and a fatty acid, which are connected via an amide bond [8]. Ceramide synthase (CERS), important enzymes in the ceramide synthesis process, acetylate sphinganine to dihydroceramide with different chain lengths, varying in lengths from C14 to C26 [9, 10]. There are six CERS www.impactjournals.com/oncotarget isoforms in mammalian cells (CERS1-6), which exert specificity for the generation of ceramides with distinct fatty acid chain lengths. CERS1 generates mainly ceramide with an 18-carbon–containing fatty acid chain (C18-ceramide) [11, 12]
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