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      Autocrine Prostaglandin E 2 Signaling Promotes Tumor Cell Survival and Proliferation in Childhood Neuroblastoma

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          Abstract

          Background

          Prostaglandin E 2 (PGE 2) is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2) has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE 2 production, the expression pattern and localization of PGE 2 receptors and intracellular signal transduction pathways activated by PGE 2.

          Principal Findings

          A high expression of the PGE 2 receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE 2 and stimulation of serum-starved neuroblastoma cells with PGE 2 increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE 2 (dmPGE 2) increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE 2. Similarly, PGE 2 receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner.

          Conclusions

          These findings demonstrate that PGE 2 acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE 2 signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation.

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          Most cited references45

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          G-protein-coupled receptors and cancer.

          G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.
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            Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

            Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk. Copyright 2005 Massachusetts Medical Society.
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              Calcium and cancer: targeting Ca2+ transport.

              Ca2+ is a ubiquitous cellular signal. Altered expression of specific Ca2+ channels and pumps are characterizing features of some cancers. The ability of Ca2+ to regulate both cell death and proliferation, combined with the potential for pharmacological modulation, offers the opportunity for a set of new drug targets in cancer. However, the ubiquity of the Ca2+ signal is often mistakenly presumed to thwart the specific therapeutic targeting of proteins that transport Ca2+. This Review presents evidence to the contrary and addresses the question: which Ca2+ channels and pumps should be targeted?
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                19 January 2012
                : 7
                : 1
                : e29331
                Affiliations
                [1 ]Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
                [2 ]Department of Clinical Pharmacology, University Hospital of North Norway, Tromsø, Norway
                [3 ]Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                [4 ]Vascular Biology Research Group, Faculty of Medicine, University of Tromsø, Tromsø, Norway
                [5 ]Division of Immunology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
                University of Navarra, Spain
                Author notes

                Conceived and designed the experiments: AR AK BK JS-S JIJ PK BS. Performed the experiments: AR AK OMF BK JS-S BS. Analyzed the data: AR AK OMF BK JS-S VG BS. Contributed reagents/materials/analysis tools: OMF VG JIJ PK BS. Wrote the paper: AR JIJ PK BS.

                Article
                PONE-D-11-10460
                10.1371/journal.pone.0029331
                3261878
                22276108
                79fcc7c1-4a00-4c23-9ead-177b851933b7
                Rasmuson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 11 June 2011
                : 25 November 2011
                Page count
                Pages: 9
                Categories
                Research Article
                Biology
                Immunology
                Immunologic Techniques
                Molecular Cell Biology
                Signal Transduction
                Signaling in Selected Disciplines
                Medicine
                Clinical Immunology
                Immunologic Techniques
                Oncology
                Basic Cancer Research
                Cancers and Neoplasms
                Pediatrics

                Uncategorized
                Uncategorized

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