Research Plan Summary: Stephen Matthew Schleicher

Project Title: The mechanism by which radiation-induced cPLA2 activation leads to signal transduction through Akt and Erk pathways in malignant glioma; finding potential therapeutic targets to increase radiation therapy efficacy.

Malignant Glioma is a fatal disease that is difficult to treat with radiation. A new enzyme, LysoPLD, was recently found to be over expressed in MG cells. This enzyme is known to convert LPC to the second messenger LPA that activates LPA receptors to initiate signal transduction through the Akt and Erk pathways in MG cells. This causes cell viability, vascular permeability, and angiogenesis. Preliminary data has shown that radiation induces cPLA2 activation and LPC production within 2 minutes in human endothelial cells. This leads to Akt and Erk phosphorylation in these cells. Moreover, mice models treated with cPLA2 inhibitors before irradiation significantly suppresses tumor growth. This experiment will investigate the role of LysoPLD in the cPLA2/LPC/Erk/Akt pathway in irradiates MG cells. We hypothesize that radiation induced LPC production acts as a substrate for LysoPLD that converts it into LPA, leading to LPA receptor activation and Akt/Erk phosphorylation. The clinical significance is that this signaling pathway involves potential therapeutic targets to improve radiation therapy efficacy in MG. The proposed project will use endothelial and MG cells to determine

1) whether LysoPLD converts radiation induced LPC to LPA in MG cells, and
2) whether LPA receptor inhibitors can interrupt radiation-induced activation of Akt/Erk and lead to decreased cell survival and function.