Introduction: The relationship between extremely aggressive cancers, like glioblastoma (GBM), and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-Lipoxygenase-1 (15-LOX-1), a linolenic acid (LA) and arachidonic acid (AA) metabolizing enzyme, induces both pro- and anti-tumorigenic effects in different cancer types. Its role in glioma activity has not yet been clearly described. This study aimed to identify and describe the influence of 15-LOX and its metabolites on glioblastoma cell activity.
Methods: Human patient samples of astrocytomas (WHO Grades II, III, IV) were examined using HPLC-MS/MS to identify the endogenous production of 15-LOX metabolites. In vitro culture of different GBM cell lines, treated exogenously with 15-LOX metabolites (13-HODE and 9-HODE) and two 15-LOX inhibitors (Luteolin and NDGA) were also examined. Dose response and viability curves, conventional and quantitative RT-PCR’s, flow cytometry, and wound healing/ transwell assays were performed to identify their influence on GBM growth, migration and, potentially, invasion.
Results: The 15-LOX pathway is present and active in GBM cell lines. Higher quantities of 13-Hydroxyoctadecadeinoic Acid (13-HODE) and 9-HODE were found in patient samples and in five GBM cell lines compared with other lipids analyzed. Both 13-HODE and 9-HODE treatments increased cell count in the tumorigenic cell line U87MG. 15-LOX inhibition using Luteolin (15-LOX-1) and NDGA (12-/15-LOX) generally decreased migration, and increased cell cycle arrest in G2/M phase.
Conclusions: 15-LOX and its LA-derived metabolites exercise a certain pro-tumorigenic influence on GBM cells in vitro. Elevated levels of HODEs found in the patients/ cell lines call attention to the possible relationship between linoleic acid metabolism and GBM. Luteolin also appears to be influencing other mechanisms impacted by 15-LOX. Further studies are needed to clarify if these relationships positively correlate with malignancy.
Patient Care: The identification of possible therapeutic targets could lead to the development of novel treatment options.
Learning Objectives: This study aimed to identify and describe the influence of 15-LOX and its metabolites on glioblastoma cell activity