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

1
Department of Cell, Developmental, and Integrative Biology, University of Birmingham at Alabama, Birmingham, AL 35233, USA
2
Research Department, Imperial College London Diabetes Centre, Abu Dhabi P.O. Box 48338, UAE
3
Comprehensive Diabetes Center, University of Birmingham at Alabama, Birmingham, AL 35294, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(10), 1357; https://doi.org/10.3390/biom10101357
Received: 31 August 2020 / Revised: 18 September 2020 / Accepted: 20 September 2020 / Published: 23 September 2020
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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. View Full-Text
Keywords: glioblastoma; sphingolipid; sphingosine-1-phosphate; sphingomyelinase; sphingomyelin; metastasis glioblastoma; sphingolipid; sphingosine-1-phosphate; sphingomyelinase; sphingomyelin; metastasis
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Hawkins, C.C.; Ali, T.; Ramanadham, S.; Hjelmeland, A.B. Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate. Biomolecules 2020, 10, 1357.

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