Cytosolic phospholipase A2 and autotaxin inhibitors as potential radiosensitizers

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Abstract

Several classes of lipid mediators are initially derived through the action of phospholipase A2 (PLA2) enzymes on phospholipids that release fatty acids and lyso- phospholipids. Both fatty acids and lysophospholipids have biological functions relevant to cancer progression. Fatty acids are metabolized to prostanoids by cyclooxygenase and leukotrienes by lipoxygenase, while lysophospholipids are metabolized to lysophosphatidic acid (LPA) by autotaxin (ATX). These metabolites modulate cellular differentiation, proliferation, apoptosis, and senescence, thereby contributing to the homeostatic control of tissue growth, remodeling, and vascularization. Tumor cells subvert these cellular functions to grow locally and to metastasize to distant sites. The deregulation of cyclooxygenase and lipoxygenase in various cancers supports role for the aberration of these two pathways in tumorigenesis. Pharmacological studies in humans have demonstrated the benefits of eicosanoid pathway intervention in certain cancers. In recent years the importance of the tumor microenvironment (TME) has become increasingly salient with respect to both tumorigenesis and response to therapy. We have focused on characterizing the role of the lysophospholipid molecules generated by PLA2, such as lysophosphatidylcholine (LPC) and its further metabolites, such as LPA, in the response of the vascular system to ionizing radiation. In normal endothelial cells, ionizing radiation rapidly induces cPLA2 activity, leading to the activation of pro-survival pathways like Akt and ERK. Inhibition of cPLA2 leads to radiosensitization and inhibition of endothelial cell-specific functions, such as cell migration, cell invasion, and tubule formation. Combined treatment with radiation and cPLA2 inhibitors resulted in delayed tumor growth. Inhibition of the extracellular enzyme involved in the generation of LPA from LPC, ATX, also inhibits endothelial-specific functions and leads to tumor radiosensitization. Finally, experiments conducted with cPLA2 knockout mice indicated that the cPLA2 deficiency within the host component resulted in delayed tumor growth and impaired tumor vascularization. The cPLA2 from the normal TME is an important mediator of tumor development and progression. Radiation-induced modifications in the TME that result in increased angiogenesis are novel targets for inhibiting pro-survival pathways in the tumor. The concurrent inhibition of inflammatory responses in normal tissues would lead to significant therapeutic gain.

Original languageEnglish
Title of host publicationPhospholipases in Health and Disease
PublisherSpringer New York
Pages159-176
Number of pages18
Volume10
ISBN (Electronic)9781493904648
ISBN (Print)9781493904631
DOIs
StatePublished - Jan 1 2014

Keywords

  • Autotaxin
  • Phospholipase A2
  • Radiosensitization
  • Radiotherapy
  • Tumor microenvironment
  • Tumor vasculature

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    Thotala, D., Laszlo, A., & Hallahan, D. E. (2014). Cytosolic phospholipase A2 and autotaxin inhibitors as potential radiosensitizers. In Phospholipases in Health and Disease (Vol. 10, pp. 159-176). Springer New York. https://doi.org/10.1007/978-1-4939-0464-8_10