Title: Normoxic cells remotely regulate the acid‐base balance of cells at the hypoxic core of connexin‐coupled tumor growths
Abstract: The FASEB JournalVolume 32, Issue 1 p. 83-96 ResearchFree to Read Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths Tobias H. Dovmark, Tobias H. Dovmark Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomSearch for more papers by this authorAlzbeta Hulikova, Alzbeta Hulikova Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomSearch for more papers by this authorSteven A. Niederer, Steven A. Niederer Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, London, United KingdomSearch for more papers by this authorRichard D. Vaughan-Jones, Richard D. Vaughan-Jones Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomSearch for more papers by this authorPawel Swietach, Corresponding Author Pawel Swietach [email protected] Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomCorrespondence: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Rd., OX1 3PT Oxford, United Kingdom. E-mail: [email protected]Search for more papers by this author Tobias H. Dovmark, Tobias H. Dovmark Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomSearch for more papers by this authorAlzbeta Hulikova, Alzbeta Hulikova Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomSearch for more papers by this authorSteven A. Niederer, Steven A. Niederer Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, London, United KingdomSearch for more papers by this authorRichard D. Vaughan-Jones, Richard D. Vaughan-Jones Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomSearch for more papers by this authorPawel Swietach, Corresponding Author Pawel Swietach [email protected] Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United KingdomCorrespondence: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Rd., OX1 3PT Oxford, United Kingdom. E-mail: [email protected]Search for more papers by this author First published: 07 September 2017 https://doi.org/10.1096/fj.201700480rRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract ATP fuels the removal of metabolic end-products, including H+ ions that profoundly modulate biological activities. Energetic resources in hypoxic tumor regions are constrained by low-yielding glycolysis, and any means of reducing the cost of acid extrusion, without compromising pH homeostasis, would therefore be advantageous for cancer cells. Some cancers express connexin channels that allow solute exchange between cells, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3_ ions. This hypothesis was tested by imaging cytoplasmic pH in spheroidal tissue growths of connexin43-positive pancreatic cancer Colo357 cells during light-controlled H+ uncaging at the hypoxic core. Cytoplasmic acid retention at the core was halved in the presence of CO2/HCO3−, but this process requires a restorative HCO3− flux. The effect of CO2/HCO3− was ablated by connexin43 inhibition or knockdown. In connexin-decoupled spheroids, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), an inhibitor of HCO3− uptake, had no effect on cytoplasmic [H+]inthe H+-uncaging region, indicating that DIDS-sensitive transport is not an adequate pH-regulatory strategy therein. With intact connexin-coupling, acid retention at the core increased upon DIDS treatment, indicating that HCO3− ions are taken up actively by peripheral cells and then transmitted passively to cells at the hypoxic core. Thus, the energetic burden of pH regulation is offloaded from hypoxic cells onto metabolically altruistic normoxic neighbors.—Dovmark, T. H., Hulikova, A., Niederer, S. A., Vaughan-Jones, R. D., Swietach, P. Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths. FASEB J. 32,83-96 (2018). www.fasebj.org Supporting Information Filename Description fsb2fj201700480r-sup-0001.docxapplication/docx, 273.5 KB Supplementary Material 1 fsb2fj201700480r-sup-0002.docxapplication/docx, 244.7 KB Supplementary Material 1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume32, Issue1January 2018Pages 83-96 RelatedInformation
Publication Year: 2017
Publication Date: 2017-09-07
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 24
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