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      Possible role of hemichannels in cancer

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          Abstract

          In humans, connexins (Cxs) and pannexins (Panxs) are the building blocks of hemichannels. These proteins are frequently altered in neoplastic cells and have traditionally been considered as tumor suppressors. Alteration of Cxs and Panxs in cancer cells can be due to genetic, epigenetic and post-transcriptional/post-translational events. Activated hemichannels mediate the diffusional membrane transport of ions and small signaling molecules. In the last decade hemichannels have been shown to participate in diverse cell processes including the modulation of cell proliferation and survival. However, their possible role in tumor growth and expansion remains largely unexplored. Herein, we hypothesize about the possible role of hemichannels in carcinogenesis and tumor progression. To support this theory, we summarize the evidence regarding the involvement of hemichannels in cell proliferation and migration, as well as their possible role in the anti-tumor immune responses. In addition, we discuss the evidence linking hemichannels with cancer in diverse models and comment on the current technical limitations for their study.

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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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            Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival.

            Increases in cytosolic free Ca2+ ([Ca2+]i) represent a ubiquitous signalling mechanism that controls a variety of cellular processes, including proliferation, metabolism and gene transcription, yet under certain conditions increases in intracellular Ca2+ are cytotoxic. Thus, in using Ca2+ as a messenger, cells walk a tightrope in which [Ca2+]i is strictly maintained within defined boundaries. To adhere to these boundaries and to sustain their modified phenotype, many cancer cells remodel the expression or activity of their Ca2+ signalling apparatus. Here, we review the role of Ca2+ in promoting cell proliferation and cell death, how these processes are remodelled in cancer and the opportunities this might provide for therapeutic intervention.
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              Pannexins, a family of gap junction proteins expressed in brain.

              Database search has led to the identification of a family of proteins, the pannexins, which share some structural features with the gap junction forming proteins of invertebrates and vertebrates. The function of these proteins has remained unclear so far. To test the possibility that pannexins underlie electrical communication in the brain, we have investigated their tissue distribution and functional properties. Here, we show that two of these genes, pannexin 1 (Px1) and Px2, are abundantly expressed in the CNS. In many neuronal cell populations, including hippocampus, olfactory bulb, cortex and cerebellum, there is coexpression of both pannexins, whereas in other brain regions, e.g., white matter, only Px1-positive cells were found. On expression in Xenopus oocytes, Px1, but not Px2 forms functional hemichannels. Coinjection of both pannexin RNAs results in hemichannels with functional properties that are different from those formed by Px1 only. In paired oocytes, Px1, alone and in combination with Px2, induces the formation of intercellular channels. The functional characteristics of homomeric Px1 versus heteromeric Px1/Px2 channels and the different expression patterns of Px1 and Px2 in the brain indicate that pannexins form cell type-specific gap junctions with distinct properties that may subserve different functions.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                27 June 2014
                2014
                : 5
                : 237
                Affiliations
                [1] 1Servicio Anatomía Patológica, Clínica Alemana de Santiago, Facultad de Medicina Clinica Alemana Universidad del Desarrollo Santiago, Chile
                [2] 2Department of Pathology, Yale School of Medicine New Haven, CT, USA
                Author notes

                Edited by: Mauricio Antonio Retamal, Universidad del Desarrollo, Chile

                Reviewed by: Núria Comes, University of Barcelona, Spain; Marc Mesnil, Institute of Cellular Physiology and Biology, France; Manuel Antonio Riquelme, University of Texas Health Science Center at San Antonio, USA

                *Correspondence: Kurt A. Schalper, Servicio Anatomía Patológica, Clinica Alemana de Santiago, Av. Manquehue 1410, Segundo Subterráneo, Santiago 7630000, Chile e-mail: kurt.schalper@ 123456yale.edu ; kschalper@ 123456alemana.cl

                This article was submitted to Membrane Physiology and Membrane Biophysics, a section of the journal Frontiers in Physiology.

                †Present address: Kurt A. Schalper, Department of Pathology, Yale School of Medicine, New Haven, USA

                Article
                10.3389/fphys.2014.00237
                4073485
                25018732
                c99a2fd8-ab61-468d-b2f2-a37aeee9c912
                Copyright © 2014 Schalper, Carvajal-Hausdorf and Oyarzo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 January 2014
                : 09 June 2014
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 210, Pages: 18, Words: 16223
                Categories
                Physiology
                Hypothesis and Theory Article

                Anatomy & Physiology
                hemichannels,connexins,pannexins,cancer
                Anatomy & Physiology
                hemichannels, connexins, pannexins, cancer

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