• 2018-07
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  • 2019-08
  • PGE EP activation has been found to


    PGE2-EP4 activation has been found to attenuate the activation of microglia and to prevent lipid peroxidation and pro-inflammatory gene expression in a murine model of lipopolysaccharide (LPS)-induced A 83-01 inflammation [15]. Moreover, PGE2/EP4 signaling has elicited a protective function in reducing injury and improving functional recovery after stroke via dual and independent cell-specific mechanisms of neuroprotection and enhanced vascular perfusion [14]. In contrast, genetic and pharmacologic inhibition of EP4 receptor, via EP4 deficiency or antagonist respectively, in a murine mouse model of Alzheimer\'s disease decreased amyloid-β levels in the brain and improved the behavioral performance of the animals [17]. EP4 receptors are the most widely expressed PGE2 receptors in the body [13], and the various biological effects observed due to PGE2 signaling via EP4 may be mediated by the externalization of EP4 to the plasma membrane and growth cones. Although the observed trafficking of the EP4 receptor to the plasma membrane induced by PGE2 and the EP4-specific agonist is compelling, the potential contribution of remaining EP receptors needs to be considered as well. In summary, these results confirm that the EP4 externalization from the Golgi apparatus to the plasma membrane in NE-4C stem cells is PGE2-induced. Furthermore, this study provides the first evidence that PGE2 can also enhance the growth cone localization of the EP4 receptor in differentiating NE-4C neuronal cells. Our results show that the important role of the PGE2/EP4 pathway in the developing nervous system may depend on the subcellular localization of the EP4 receptor.
    Acknowledgements This study was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) (grant #341493-2012).
    The prostanoid EP4 receptor is one of four G-protein-coupled receptors (EP1-4) that mediate the action of prostaglandin E2 (PGE2), a hormone-like lipid molecule produced by the actions of cyclooxygenases and PGE synthase on arachidonic acid. EP4 receptor is widely expressed throughout the body including the gastrointestinal tract, lung, heart, kidney, sensory neurons, spleen, leukocytes and platelets., , , , , EP4 receptor signaling is associated with pain, inflammation, vasodilation, bone remodeling, and gastrointestinal homeostasis., , In the past fifteen years, EP4 receptor has been gradually recognized as a promising therapeutic target of cancer., , EP4 receptor is overexpressed in a variety of malignancies including prostate, breast, colon, and lung cancers., , , , , In addition, activation of EP4 receptor induces angiogenesis, and proliferation and metastasis of cancer cells., , To block these effects, highly potent and selective EP4 receptor antagonists were developed., , Among them, CJ-023423 (also called AAT-007 or RQ-07, ) is currently under a phase II clinical trial for the therapy of advanced solid tumours including prostate, breast and lung cancer., Positron emission tomography (PET) is a powerful molecular imaging modality that utilizes positron-emitter-tagged tracers to acquire physiological/pathological information in living subjects. PET is non-invasive and highly sensitive, and has quantification capability. The most popular oncologic PET tracer is F-labeled 2-fluoro-2-deoxy-glucose (F-FDG), which is used to measure glycolytic activity. F-FDG is routinely used in the clinics for diagnosis, prognosis, and monitoring treatment response of cancer., , With a promising antagonist currently under clinical trial, the ability to identify EP4-receptor-positive cancer patients for treatment and to monitor treatment response will greatly advance the applications of EP4-targeted therapies. To our knowledge, no EP4 receptor targeting radiotracer has been reported in literature. Therefore, we initiated our efforts on the development of EP4 receptor PET tracers, and selected an antagonist CJ-042794 as a candidate for radiolabeling. CJ-042794 () was selected due to its selectivity for EP4 receptor over EP1-3 (K(EP4): 3nM; K values for EP1-3: >1000nM). In addition, the fluoro group in its structure could be replaced with F, the most popular PET isotope that has a suitable half-life (109.7min) for imaging and could be produced easily by a medical cyclotron. F also decays dominantly by positron emission (97%), and has relatively low positron energy (0.64MeV), leading to high-resolution PET images.