Lipid Mediators as Therapeutic Targets in Prostate Cancer

Abstract

Lipid mediators are small molecules, derived from lipid metabolism, that initiate cellular responses. In this review, the major classes of lipid mediators are considered with respect to their effects on prostate cancer cells. These classes are: sphingolipids (sphingosine 1-phosphate and ceramide), glycophospholipids (lysophosphatidic acid; LPA), eicosanoids (prostaglandins, thromboxanes, and leukotrienes), cannabinoids, and free fatty acids. Almost all of these mediators elicit effects by binding to druggable G protein-coupled receptors (GPCRs) to initiate cell proliferation, stimulate migration, and enhance survival. The exceptions are omega-3 fatty acids and endocannabinoids, which inhibit proliferation. The mediators and their receptors serve as potential targets for (1) enzyme inhibitors that block their synthesis, or (2) GPCR antagonists or agonists. These agents are in various stages of development. Progress in testing their translational potential varies between the mediator classes. Lipid mediators also show potential as diagnostic or prognostic biomarkers. Interesting mechanistic aspects have been identified in the course of studying lipid mediator responses in prostate cancer cells. These include positive cross-talk between LPA receptors and EGF receptors, and negative cross-talk between LPA receptors and free fatty acid (FFA) receptors. Together, these findings suggest new strategies for modulating prostate cancer growth and survival pathways in a therapeutic direction.