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

Biomolecules. 2020 Sep 23;10(10):1357. doi: 10.3390/biom10101357.

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.

Keywords: glioblastoma; metastasis; sphingolipid; sphingomyelin; sphingomyelinase; sphingosine-1-phosphate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary
  • Cell Proliferation / genetics
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism
  • Neoplasm Metastasis
  • Phospholipase D / genetics
  • Sphingolipids / genetics
  • Sphingolipids / metabolism*
  • Sphingomyelin Phosphodiesterase / genetics*
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / genetics
  • Sphingosine / metabolism
  • Type C Phospholipases / genetics

Substances

  • Lysophospholipids
  • Sphingolipids
  • sphingosine 1-phosphate
  • Type C Phospholipases
  • Sphingomyelin Phosphodiesterase
  • Phospholipase D
  • Sphingosine