Opposing roles of PGD2 in GBM

Abstract

Background: The World Health Organization classifies glioblastoma (GBM) as a grade IV astrocytoma. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. GBM cells produce significant levels of various types of bioactive lipids. Prostaglandin D₂ (PGD₂) influences both pro- and anti-tumorigenic activities in the cell; however, its role in GBM is unclear. Therefore, this study aimed to identify the impact of PGD₂ on GBM cell activities in vitro.

Methods: First we looked to identify the presence of the PGD₂ synthesis pathway through RT-PCR, immunohistochemistry, and HPLC-MS/MS in three GBM cell lines. Then, to observe PGD₂'s effects on cell count and apoptosis/mitosis (Hoechst 33342 stain), and migration (Transwell Assay), the cells were treated in vitro with physiological (<1μM) and/or supraphysiological (>1μM) concentrations of PGD₂ over 72h. HPLC-MS/MS was used to identify the lipid composition of patients with either Grade II/III gliomas or GBM.

Results: We identified the presence of endogenous PGD₂ with its corresponding enzymes and receptors. Exogenous PGD₂ both increased cell count (<1μM) and decreased cell count (10μM) in a concentration-dependent manner. There were no significant effects on apoptosis. A significant decrease in mitotic activity was seen only in U251MG, and a significant increase was seen in migration with 5μM PGD₂ treatments. A very significant increase of PGD₂ was seen from Grade II/III gliomas to GBM.

Conclusions: Our study demonstrates that prostaglandin D₂ possesses a dynamic, concentration-dependent effect in GBM cell activities. The increase of PGD₂ production in GBM patients suggests a pro-tumorigenic role of PGD₂ in glioma growth and invasion. Therefore, prostaglandin signaling in GBM requires further investigation to identify new targets for more effective therapies.