Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

Abstract

Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood–brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…Many studies have suggested that the SphK1/S1P axis could play a role in the promotion of several types of tumors, based on the overexpression of SphK1 in tumor cell lines and in patient samples, and sometimes, on the measured increased S1P levels in tumors and/or in patient blood. These studies have recently been reviewed for breast [ 46 ], ovarian, [ 47 ], and gastrointestinal cancers [ 48 ], hepatocellular carcinoma [ 49 ], melanoma [ 50 ] and glioblastoma [ 51 ]. High S1P in breast tumor tissue is significantly associated with lymphnode metastasis [ 52 ].…”

Targeting Immunometabolism in Glioblastoma

“…Activation of S1PRs results in cellular proliferation and further production of S1P to promote cell motility and survival. This tight linkage of interconnected pathways for the rapid synthesis and breakdown of ceramide (pro-apoptotic) and S1P (pro-survival) has given rise to the "sphingolipid rheostat" model, in which the balance of these two biomolecules plays an important and potentially targetable role in normal cellular function and oncogenesis (127)(128)(129)(130)(131).…”

“…In gliomas, this shift is likely due to multiple alterations in sphingolipid synthesis, including increased expression of SK1 (134)(135)(136), deletion of c h r o m o s o m a l r e g i o n s c o n t a i n i n g S P L ( 1 3 7 ) , a n d downregulation of S1P phosphatase 2 (138), resulting in increased S1P levels; as well as inhibition of ceramide synthase (139) and increased expression of ceramidases (134). The activity of SMases in glioblastoma is still being elucidated, but it has been shown that acid SMase may sensitize glioma cells to chemotherapy and radiation by increasing metabolism of sphingomyelin to ceramide and consequent apoptosis in the context of p53-deficiency; conversely, neutral SMase may be involved in increasing ceramide production in p53-wildtype cells (129). Increased understanding of the proapoptotic role of SMases in glioblastoma may yield new therapeutic targets.…”

“…Sphingolipid synthesis occurs de novo via condensation of serine and palmitate to 3-keto-dyhydrosphingosine, which via several intermediate steps involving ceramide synthases (CERS1-6) is converted to ceramide, a molecule well-identified as a pro-apoptotic signal ( 128 , 129 ). Ceramide consists of an 18-carbon sphingosine long-chain base that contains an amide-linkage to a fatty acyl chain of variable carbon number; synthesis by CERS1-6 is the rate-limiting step of de novo ceramide synthesis and each enzyme is responsible for ceramides of specific fatty acyl chain length.…”

Phospholipases: From Structure to Biological Function

“…Cells can evade apoptosis by converting ceramide to sphingosine-1-phosphate. In this regard, Hawkins et al [ 24 ] discuss the role of sphingomyelinases and sphingosine 1-phosphate in glioblastoma and metastatic brain tumors. There are two main types of sphingomyelinases: neutral and acid.…”