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The Role and Function of Sphingolipids in Glioblastoma Multiforme

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Bioactive Sphingolipids in Cancer Biology and Therapy

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Abstract

Aberrations in sphingolipid metabolism and thus levels have been implicated in promoting the aggressiveness of glioblastoma multiforme, one of the most lethal cancers in humans. A major player is sphingosine-1-phosphate, that pressures GBM cells to exhibit its hallmarks, leading to increased proliferation, invasiveness, stemness, angiogenesis and death resistance, this indicating a fine balance and interplay between S1P function and this malignancy. To the opposite GBM are organized to maintain low their ceramide and sphingomyelin levels, which in turn lead to a loss of growth control and to a gain of death resistance. While the mechanisms of these alterations are emerging, the sphingolipid signaling pathway has been implicated in controlling GBM action and mass, and in mediating the link of malignancy. Here we describe and discuss the current understanding on how GBM cells arm themselves with the abilities of manipulating sphingolipids, especially sphingosine-1-phosphate and ceramide, and how these alterations, through differential interactions, regulate different signaling pathways, and integrate GBM function and mass, thus providing molecular cues for GBM properties and progression. It is a future challenge unrevealing how the multiforme features of sphingolipid signaling could be effectively manipulated as strategies to optimize the efficacy and selectivity of future therapies for GBM.

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Abbreviations

2OHOA:

2-Hydroxyoleic acid

A-ceramidase:

Acid ceramidase

A-SMase:

Acid sphingomyelinase

Bcl2L13:

B-cell lymphoma 2-like 13

bFGF:

Basic fibroblast growth factor

CD95L:

CD95 ligand

CerS:

Ceramide synthase

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

ER:

Endoplasmic reticulum

GlcCer:

Glucosylceramide

GSCs:

Glioblastoma stem-like cells

HIF:

Hypoxia inducible factor

IL:

Interleukin

N-SMase:

Neutral sphingomyelinase

PAI-1:

Plasminogen activator inhibitor-1

PAS:

Plasminogen activator system

PERK:

Protein kinase R-like endoplasmic reticulum kinase

PKCδ:

Protein kinase C delta

PLD:

Phospholipase D

PRKD2:

Protein kinase D2

PTEN:

Phosphatase and tensin homolog located on chromosome TEN

S1P:

Sphingosine-1-phosphate

S1P1–5 :

Sphingosine-1-phosphate receptors 1–5

SPP2:

Sphingosine-1-phosphate phosphatase 2

THC:

Tetrahydrocannabinol

TMZ:

Temozolomide

TNFα:

Tumor necrosis factor α

VEGF:

Vascular endothelial growth factor

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    Authors and Affiliations

    1. Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy

      Loubna Abdel Hadi & Clara Di Vito

    2. Neurosurgery Unit, Laboratory of Experimental Neurosurgery and Cell Therapy, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

      Giovanni Marfia & Stefania Elena Navone

    3. Neurosurgical Unit, San Carlo Borromeo Hospital, Milan, Italy

      Rolando Campanella

    4. Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, via Fratelli Cervi, 93, 20090, Segrate, Milan, Italy

      Laura Riboni

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    1. Loubna Abdel Hadi
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    2. Clara Di Vito
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    3. Giovanni Marfia
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    4. Stefania Elena Navone
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    5. Rolando Campanella
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    6. Laura Riboni
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    Correspondence to Laura Riboni .

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    Editors and Affiliations

    1. Stony Brook University, Stony Brook Cancer Center, Stony Brook, New York, USA

      Yusuf A. Hannun

    2. Dept. of Physiology & Biophysics, Stony Brook University, Stony Brook, New York, USA

      Chiara Luberto

    3. Dept. of Medicine, Stony Brook University, Stony Brook, New York, USA

      Cungui Mao

    4. Dept. of Medicine, Stony Brook University, Stony Brook, New York, USA

      Lina Marie Obeid

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    Abdel Hadi, L., Di Vito, C., Marfia, G., Navone, S.E., Campanella, R., Riboni, L. (2015). The Role and Function of Sphingolipids in Glioblastoma Multiforme. In: Hannun, Y., Luberto, C., Mao, C., Obeid, L. (eds) Bioactive Sphingolipids in Cancer Biology and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-20750-6_12

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