Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival

Abstract

The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to generate a choline headgroup and the important lipid second messenger, phosphatidic acid (PtdOH). PLD family members are found in a diverse range of species from viruses to humans and regulate many important physiological processes including cytoskeletal rearrangements, cell migration, immune response, and cell proliferation. As such, PLD promotes oncogenic processes and elevated PLD activity has been documented in many types of cancerous tissue and derived cell lines. PLD activity is associated with cell cycle progression, resistance to apoptotic stimuli, and tumor cell invasion, but the molecular mechanisms of these PLD-mediated processes are largely uncharacterized. The goal of this project was to identify and characterize novel PLD-protein complexes in order to further understand the mechanisms by which PLD promotes cancer growth and survival. In this dissertation, PLD-derived PtdOH is demonstrated to be a novel regulator of pro-survival Akt kinase in glioblastoma cells by regulating membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. Additionally, PLD is shown to interact with a number of metabolic enzymes and a potential role for the regulation of cellular bioenergetics in GBM is explored. The results of this research provide mechanistic insight into PLD-mediated cancer cell survival.