Abstract
BackgroundThe 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.MethodsConfocal 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.ResultsOur 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.ConclusionsOur 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.
Highlights
Glioblastoma multiforme (GBM), the most aggressive and frequent glioma which represents about 50% of all brain tumors, is characterized by an aberrant network of molecular signaling pathways that drive uncontrolled cell proliferation, high invasivity, aberrant angiogenesis and high cellular heterogeneity [1].Among the factors recently described to be implicated in different biological features of gliomas, an increasing attention has been focused on some chemokine/chemokine receptor axes
Our studies demonstrated that CXCR4 and Phosphatidylcholine-specific phospholipase C (PC-PLC) co-localize and are associated on U87MG cell membrane
Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology for its ability in modulating cell metabolism, glioma growth and motility, and for its inhibitory effect on crucial molecules involved in cancer progression
Summary
Glioblastoma multiforme (GBM), the most aggressive and frequent glioma which represents about 50% of all brain tumors, is characterized by an aberrant network of molecular signaling pathways that drive uncontrolled cell proliferation, high invasivity, aberrant angiogenesis and high cellular heterogeneity [1].Among the factors recently described to be implicated in different biological features of gliomas, an increasing attention has been focused on some chemokine/chemokine receptor axes. CXCR4 is a transmembrane G-protein-coupled receptor, widely expressed in several tumor types, whose binding with the chemokine CXCL12 results in the activation of down-stream signal transduction pathways such as the phosphorylation of mitogen activated protein (MAP) kinases and AKT-mediated signaling, responsible for multiple features of malignancy including chemotaxis, cell survival, cell proliferation, increased intracellular calcium and transcription of genes involved in angiogenesis, inflammation and metastasis [5, 6]. Using an in vitro and in vivo U87MG glioma model, we recently showed that CXCR4 inhibition with a novel peptide antagonist induces alterations in molecular responses strictly related to the tumor cells and modulates the reactivity of glioma-associated microglia/macrophages (GAMs), with a polarization into a proinflammatory GAMs phenotype that could be correlated with a potential anti-tumor activity [11]. 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.
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