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.
Highlights
In recent years, studies of the role of sphingolipid metabolism have become an integral part of cancer research
This has led to the concept of the sphingolipid rheostat, which illustrates the consequence of shifting the balance between ceramide and S1P on cell survival [20,21]
There is very limited knowledge on the exact convergence of sphingolipid metabolism and phospholipase signaling in metastatic cancers, to the brain, but investigations in other cancers and of the pathways independently suggest that this will be a very active area of exploration in upcoming years
Summary
Studies of the role of sphingolipid metabolism have become an integral part of cancer research. Samples from GBM patients have shown an increase in S1P concurrent with a decrease in ceramides, as compared with normal brain, indicating tilting of the sphingolipid rheostat toward a pro-tumor phenotype [10]. Subsequent studies found that overexpression of acid SMase increased ceramide levels but failed to sensitize GBM cells to radiation or chemotherapy with TMZ, the current standard of care [61]. Activation of neutral SMase in C6 glioma cells has been suggested to an increase in mitogen-activated protein kinase (MAPK) activation through upregulation of ceramides, leading to apoptosis [67]. Together, these data suggest that SMases can regulate ceramide levels and apoptosis in glioma cells, with differential responses, in part, due to p53
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