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

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.

Phosphatidylcholine-specific phospholipase C inhibition reduces HER2-overexpression, cell proliferation andin vivotumor growth in a highly tumorigenic ovarian cancer model

“…Agents affecting HER2 expression and mechanisms of HER2 endocytosis and recycling may therefore have profound effects on HER2-driven oncogenic signaling transduction [ 12 ]. Although detailed investigations on the effects of D609 on HER2-driven oncogenic signaling pathways were out of the scope of the present study, our Western blot experiments confirmed high levels of constitutive Akt phosphorylation in untreated SKOV3.ip cells, and showed decreases in the levels of pAKT and mTOR in cells exposed to D609 for 24 h. Interestingly, we recently reported that PC-PLC inhibition by D609 also induced downmodulation of the CXCR4 receptor in U87MG glioma cells, an effect which was similarly associated with remarkable decreases in AKT phosphorylation and reduced cell proliferation [ 35 ]. The MAPK phosphorylation levels were instead maintained rather high in D609-treated SKOV3.ip cells (84 ± 3% versus untreated controls at 24–72 h), likely due to the reported constitutive Ras activation present in these cells [ 30 ].…”

Double-Targeted Knockdown of miR-21 and CXCR4 Inhibits Malignant Glioma Progression by Suppression of the PI3K/AKT and Raf/MEK/ERK Pathways

“…Numerous studies suggest that the overexpression of CXCR4 facilitates proliferation, angiogenesis, invasion, and metastasis, as well as chemotherapy and radiotherapy resistance of glioma in several glioma cell lines and mouse models [ 16 – 21 ]. Administration of either CXCR4 neutralizing antibody or CXCR4 siRNA impairs the enhanced glioma malignancy (proliferation, angiogenesis, invasion, metastasis, and postchemotherapy and postradiotherapy recurrence) and increases median survival in vivo glioma models [ 17 – 20 , 22 – 27 ]. Thus, the potential of CXCR4 as an antitumor target has been a popular research topic.…”

Development of a novel morphological paclitaxel-loaded PLGA microspheres for effective cancer therapy: in vitro and in vivo evaluations

“…As delivery carriers of PTX, their morphology has significant influences on drug entrapment and release behaviors, which further affects antitumor activity (Wang et al., 2015 ). Furthermore, the disruption of programed cell proliferation signaling pathways may result in elevated cell death, so the changes of molecule biology in glioma cells play important roles in malignant glioma treatment (Mercurio et al., 2017 ).…”