Influence of Lipoxygenase Inhibition on Glioblastoma Cell Biology.

Felipe Da Costa Souza,Matthew Thomas Ferreira,Alison Colquhoun

doi:10.3390/ijms21218395

Felipe Da Costa Souza, Matthew Thomas Ferreira + Show 1 more

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https://doi.org/10.3390/ijms21218395

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Abstract

Background: The relationship between glioblastoma (GBM) and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-lipoxygenase-1 (15-LOX), a linolenic acid and arachidonic acid metabolizing enzyme, induces both pro- and antitumorigenic effects in different cancer types. Its role in glioma activity has not yet been clearly described. The objective of this study was to identify the influence of 15-LOX and its metabolites on glioblastoma cell activity. Methods: GBM cell lines were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify 15-LOX metabolites. GBM cells treated with 15-LOX metabolites, 13-hydroxyoctadecadeinoic acid (HODE) and 9-HODE, and two 15-LOX inhibitors (luteolin and nordihydroguaiaretic acid) were also examined. Dose response/viability curves, RT-PCRs, flow cytometry, migration assays, and zymograms were performed to analyze GBM growth, migration, and invasion. Results: Higher quantities of 13-HODE were observed in five GBM cell lines compared to other lipids analyzed. Both 13-HODE and 9-HODE increased cell count in U87MG. 15-LOX inhibition decreased migration and increased cell cycle arrest in the G2/M phase. Conclusion: 15-LOX and its linoleic acid (LA)-derived metabolites exercise a protumorigenic influence on GBM cells in vitro. Elevated endogenous levels of 13-HODE called attention to the relationship between linoleic acid metabolism and GBM cell activity.

Highlights

Glioblastoma (GBM) is a grade IV astrocyte-derived tumor and the most aggressive type of glioma, corresponding to 65% of identified gliomas [1]
The roles of n-3 and n-6 polyunsaturated fatty acid (PUFA) metabolisms upon cell signaling, inflammation, metabolism, and proliferation have been extensively studied over the past years [6,7]
PUFAs, metabolized by cyclooxygenase (COX), lipoxygenases (LOX), and/or cytochrome P450 enzymes, produce molecules that can act as signals in a range of physiological and pathological processes, including cancer [8,9,10]

Summary

Introduction

Glioblastoma (GBM) is a grade IV astrocyte-derived tumor and the most aggressive type of glioma, corresponding to 65% of identified gliomas [1]. The roles of n-3 and n-6 polyunsaturated fatty acid (PUFA) metabolisms upon cell signaling, inflammation, metabolism, and proliferation have been extensively studied over the past years [6,7]. Despite their known biological functions, PUFAs are substrates for the synthesis of lipid-derived molecules collectively called oxylipins. Results: Higher quantities of 13-HODE were observed in five GBM cell lines compared to other lipids analyzed. Both 13-HODE and 9-HODE increased cell count in U87MG. Elevated endogenous levels of 13-HODE called attention to the relationship between linoleic acid metabolism and GBM cell activity

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