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      Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

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          Abstract

          After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin’s chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

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          Most cited references126

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          Points of control in inflammation.

          Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
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            Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.

            Acetylation of proteins on lysine residues is a dynamic posttranslational modification that is known to play a key role in regulating transcription and other DNA-dependent nuclear processes. However, the extent of this modification in diverse cellular proteins remains largely unknown, presenting a major bottleneck for lysine-acetylation biology. Here we report the first proteomic survey of this modification, identifying 388 acetylation sites in 195 proteins among proteins derived from HeLa cells and mouse liver mitochondria. In addition to regulators of chromatin-based cellular processes, nonnuclear localized proteins with diverse functions were identified. Most strikingly, acetyllysine was found in more than 20% of mitochondrial proteins, including many longevity regulators and metabolism enzymes. Our study reveals previously unappreciated roles for lysine acetylation in the regulation of diverse cellular pathways outside of the nucleus. The combined data sets offer a rich source for further characterization of the contribution of this modification to cellular physiology and human diseases.
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              The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.

              NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response.
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                Author and article information

                Contributors
                AOrnelas@mdanderson.org
                smillward@mdanderson.or
                Journal
                Cancer Metastasis Rev
                Cancer Metastasis Rev
                Cancer Metastasis Reviews
                Springer US (New York )
                0167-7659
                1573-7233
                31 July 2017
                31 July 2017
                2017
                : 36
                : 2
                : 289-303
                Affiliations
                [1 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Cancer Systems Imaging, Division of Diagnostic Imaging, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [2 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [3 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Epidemiology, Division of Cancer Prevention and Population Sciences, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [4 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, McGovern Medical School, Department of Integrative Biology and Pharmacology, , The University of Texas Health Science Center at Houston, ; Houston, TX USA
                [5 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Systems Biology, Proteomics and Metabolomics Facility, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [6 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Clinical Cancer Prevention, Division of OVP, Cancer Prevention and Population Sciences, , The University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                Article
                9675
                10.1007/s10555-017-9675-z
                5557878
                28762014
                c7441be1-dd1c-489d-9c81-d8b3c16ce640
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                Custom metadata
                © Springer Science+Business Media, LLC 2017

                Oncology & Radiotherapy
                platelets,aspirin,cyclooxygenase-1,cyclooxygenase-2,chemoprevention,acetylome
                Oncology & Radiotherapy
                platelets, aspirin, cyclooxygenase-1, cyclooxygenase-2, chemoprevention, acetylome

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