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      The Role of Neurokinin-1 Receptor in the Microenvironment of Inflammation and Cancer

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          Abstract

          The recent years have witnessed an exponential increase in cancer research, leading to a considerable investment in the field. However, with few exceptions, this effort has not yet translated into a better overall prognosis for patients with cancer, and the search for new drug targets continues. After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a wide variety of functions. Antagonists against the NK-1 receptor are safe clinical drugs that are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects. Recently, it has become apparent that SP can induce tumor cell proliferation, angiogenesis, and migration via the NK-1 receptor, and that the SP/NK-1 receptor complex is an integral part of the microenvironment of inflammation and cancer. Therefore, the use of NK-1 receptor antagonists as a novel and promising approach for treating patients with cancer is currently under intense investigation. In this paper, we evaluate the recent scientific developments regarding this receptor system, its role in the microenvironment of inflammation and cancer, and its potentials and pitfalls for the usage as part of modern anticancer strategies.

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          Most cited references 245

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          Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.

          Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.
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            The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.

            The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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              Regulation of neuronal survival by the serine-threonine protein kinase Akt.

              A signaling pathway was delineated by which insulin-like growth factor 1 (IGF-1) promotes the survival of cerebellar neurons. IGF-1 activation of phosphoinositide 3-kinase (PI3-K) triggered the activation of two protein kinases, the serine-threonine kinase Akt and the p70 ribosomal protein S6 kinase (p70(S6K)). Experiments with pharmacological inhibitors, as well as expression of wild-type and dominant-inhibitory forms of Akt, demonstrated that Akt but not p70(S6K) mediates PI3-K-dependent survival. These findings suggest that in the developing nervous system, Akt is a critical mediator of growth factor-induced neuronal survival.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                The Scientific World Journal
                1537-744X
                2012
                1 April 2012
                : 2012
                Affiliations
                1Research Laboratory on Neuropeptides, Hospital Infantil Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013 Seville, Spain
                2Department of Pediatric Infectious Diseases and Immunology, Hospital Infantil Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013 Seville, Spain
                3Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstrasse 4, 80337 Munich, Germany
                Author notes

                Academic Editors: D. A. Altomare and A. K. Kiemer

                Article
                10.1100/2012/381434
                3322385
                22545017
                Copyright © 2012 Marisa Rosso et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Review Article

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