Phosphatidylcholine-specific phospholipase C inhibition down- regulates CXCR4 expression and interferes with proliferation, invasion and glycolysis in glioma cells

L. Mercurio, S. Cecchetti, A. Ricci, A. Pacella, G. Cigliana, G. Bozzuto, F. Podo, E. Iorio, G. Carpinelli

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

BACKGROUND: The chemokine receptor CXCR4 plays a crucial role in tumors, including glioblastoma multiforme (GBM), the most aggressive glioma. Phosphatidylcholine-specific phospholipase C (PC-PLC), a catabolic enzyme of PC metabolism, is involved in several aspects of cancer biology and its inhibition down-modulates the expression of growth factor membrane receptors interfering with their signaling pathways. In the present work we investigated the possible interplay between CXCR4 and PC-PLC in GBM cells. METHODS: Confocal microscopy, immunoprecipitation, western blot analyses, and the evaluation of migration and invasion potential were performed on U87MG cells after PC-PLC inhibition with the xanthate D609. The intracellular metabolome was investigated by magnetic resonance spectroscopy; lactate levels and lactate dehydrogenase (LDH) activity were analyzed by colorimetric assay. RESULTS: Our studies demonstrated that CXCR4 and PC-PLC co-localize and are associated on U87MG cell membrane. D609 reduced CXCR4 expression, cell proliferation and invasion, interfering with AKT and EGFR activation and expression. Metabolic analyses showed a decrease in intracellular lactate concentration together with a decrement in LDH activity. CONCLUSIONS: Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology not only for its ability in modulating cell metabolism, glioma growth and motility, but also for its inhibitory effect on crucial molecules involved in cancer progression.
Original languageEnglish
Pages (from-to)e0176108
JournalPLoS One
Volume12
Issue number4
DOIs
Publication statusPublished - Apr 19 2017

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phospholipase C
glycolysis
Glycolysis
Glioma
phosphatidylcholines
Down-Regulation
Glioblastoma
lactate dehydrogenase
L-Lactate Dehydrogenase
Metabolism
neoplasms
lactates
cells
Lactic Acid
Magnetic resonance spectroscopy
Biological Sciences
metabolome
Neoplasms
cell invasion
metabolism

Keywords

  • Bridged-Ring Compounds/pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation
  • Glycolysis/drug effects/genetics
  • Humans
  • L-Lactate Dehydrogenase/genetics/metabolism
  • Lactic Acid/metabolism
  • Metabolome/genetics
  • Neuroglia/drug effects/metabolism/pathology
  • Phosphodiesterase Inhibitors/pharmacology
  • Proto-Oncogene Proteins c-akt/genetics/metabolism
  • Receptor, Epidermal Growth Factor/genetics/metabolism
  • Receptors, CXCR4/genetics/metabolism
  • Signal Transduction
  • Thiones/pharmacology
  • Type C Phospholipases/antagonists & inhibitors/genetics/metabolism

Cite this

Phosphatidylcholine-specific phospholipase C inhibition down- regulates CXCR4 expression and interferes with proliferation, invasion and glycolysis in glioma cells. / Mercurio, L.; Cecchetti, S.; Ricci, A.; Pacella, A.; Cigliana, G.; Bozzuto, G.; Podo, F.; Iorio, E.; Carpinelli, G.

In: PLoS One, Vol. 12, No. 4, 19.04.2017, p. e0176108.

Research output: Contribution to journalArticle

Mercurio, L. ; Cecchetti, S. ; Ricci, A. ; Pacella, A. ; Cigliana, G. ; Bozzuto, G. ; Podo, F. ; Iorio, E. ; Carpinelli, G. / Phosphatidylcholine-specific phospholipase C inhibition down- regulates CXCR4 expression and interferes with proliferation, invasion and glycolysis in glioma cells. In: PLoS One. 2017 ; Vol. 12, No. 4. pp. e0176108.
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abstract = "BACKGROUND: The chemokine receptor CXCR4 plays a crucial role in tumors, including glioblastoma multiforme (GBM), the most aggressive glioma. Phosphatidylcholine-specific phospholipase C (PC-PLC), a catabolic enzyme of PC metabolism, is involved in several aspects of cancer biology and its inhibition down-modulates the expression of growth factor membrane receptors interfering with their signaling pathways. In the present work we investigated the possible interplay between CXCR4 and PC-PLC in GBM cells. METHODS: Confocal microscopy, immunoprecipitation, western blot analyses, and the evaluation of migration and invasion potential were performed on U87MG cells after PC-PLC inhibition with the xanthate D609. The intracellular metabolome was investigated by magnetic resonance spectroscopy; lactate levels and lactate dehydrogenase (LDH) activity were analyzed by colorimetric assay. RESULTS: Our studies demonstrated that CXCR4 and PC-PLC co-localize and are associated on U87MG cell membrane. D609 reduced CXCR4 expression, cell proliferation and invasion, interfering with AKT and EGFR activation and expression. Metabolic analyses showed a decrease in intracellular lactate concentration together with a decrement in LDH activity. CONCLUSIONS: Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology not only for its ability in modulating cell metabolism, glioma growth and motility, but also for its inhibitory effect on crucial molecules involved in cancer progression.",
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T1 - Phosphatidylcholine-specific phospholipase C inhibition down- regulates CXCR4 expression and interferes with proliferation, invasion and glycolysis in glioma cells

AU - Mercurio, L.

AU - Cecchetti, S.

AU - Ricci, A.

AU - Pacella, A.

AU - Cigliana, G.

AU - Bozzuto, G.

AU - Podo, F.

AU - Iorio, E.

AU - Carpinelli, G.

N1 - LR: 20170505; JID: 101285081; 0 (Bridged-Ring Compounds); 0 (CXCR4 protein, human); 0 (Phosphodiesterase Inhibitors); 0 (Receptors, CXCR4); 0 (Thiones); 33X04XA5AT (Lactic Acid); 83373-60-8 (tricyclodecane-9-yl-xanthogenate); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.4.- (Type C Phospholipases); EC 3.1.4.3 (phosphatidylcholine-specific phospholipase C); 2016/12/14 [received]; 2017/04/05 [accepted]; epublish

PY - 2017/4/19

Y1 - 2017/4/19

N2 - BACKGROUND: The chemokine receptor CXCR4 plays a crucial role in tumors, including glioblastoma multiforme (GBM), the most aggressive glioma. Phosphatidylcholine-specific phospholipase C (PC-PLC), a catabolic enzyme of PC metabolism, is involved in several aspects of cancer biology and its inhibition down-modulates the expression of growth factor membrane receptors interfering with their signaling pathways. In the present work we investigated the possible interplay between CXCR4 and PC-PLC in GBM cells. METHODS: Confocal microscopy, immunoprecipitation, western blot analyses, and the evaluation of migration and invasion potential were performed on U87MG cells after PC-PLC inhibition with the xanthate D609. The intracellular metabolome was investigated by magnetic resonance spectroscopy; lactate levels and lactate dehydrogenase (LDH) activity were analyzed by colorimetric assay. RESULTS: Our studies demonstrated that CXCR4 and PC-PLC co-localize and are associated on U87MG cell membrane. D609 reduced CXCR4 expression, cell proliferation and invasion, interfering with AKT and EGFR activation and expression. Metabolic analyses showed a decrease in intracellular lactate concentration together with a decrement in LDH activity. CONCLUSIONS: Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology not only for its ability in modulating cell metabolism, glioma growth and motility, but also for its inhibitory effect on crucial molecules involved in cancer progression.

AB - BACKGROUND: The chemokine receptor CXCR4 plays a crucial role in tumors, including glioblastoma multiforme (GBM), the most aggressive glioma. Phosphatidylcholine-specific phospholipase C (PC-PLC), a catabolic enzyme of PC metabolism, is involved in several aspects of cancer biology and its inhibition down-modulates the expression of growth factor membrane receptors interfering with their signaling pathways. In the present work we investigated the possible interplay between CXCR4 and PC-PLC in GBM cells. METHODS: Confocal microscopy, immunoprecipitation, western blot analyses, and the evaluation of migration and invasion potential were performed on U87MG cells after PC-PLC inhibition with the xanthate D609. The intracellular metabolome was investigated by magnetic resonance spectroscopy; lactate levels and lactate dehydrogenase (LDH) activity were analyzed by colorimetric assay. RESULTS: Our studies demonstrated that CXCR4 and PC-PLC co-localize and are associated on U87MG cell membrane. D609 reduced CXCR4 expression, cell proliferation and invasion, interfering with AKT and EGFR activation and expression. Metabolic analyses showed a decrease in intracellular lactate concentration together with a decrement in LDH activity. CONCLUSIONS: Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology not only for its ability in modulating cell metabolism, glioma growth and motility, but also for its inhibitory effect on crucial molecules involved in cancer progression.

KW - Bridged-Ring Compounds/pharmacology

KW - Cell Line, Tumor

KW - Cell Movement

KW - Cell Proliferation

KW - Gene Expression Regulation

KW - Glycolysis/drug effects/genetics

KW - Humans

KW - L-Lactate Dehydrogenase/genetics/metabolism

KW - Lactic Acid/metabolism

KW - Metabolome/genetics

KW - Neuroglia/drug effects/metabolism/pathology

KW - Phosphodiesterase Inhibitors/pharmacology

KW - Proto-Oncogene Proteins c-akt/genetics/metabolism

KW - Receptor, Epidermal Growth Factor/genetics/metabolism

KW - Receptors, CXCR4/genetics/metabolism

KW - Signal Transduction

KW - Thiones/pharmacology

KW - Type C Phospholipases/antagonists & inhibitors/genetics/metabolism

U2 - 10.1371/journal.pone.0176108 [doi]

DO - 10.1371/journal.pone.0176108 [doi]

M3 - Article

VL - 12

SP - e0176108

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

ER -