Inhibition of lactate export by genetic disruption of MCT/basigin complex sensitizes tumor cells to phenformin

Abstract

Event Abstract Back to Event Inhibition of lactate export by genetic disruption of MCT/basigin complex sensitizes tumor cells to phenformin Ibtissam Marchiq1, Renaud Le Floch1, Sara Granja2, Daniele Roux1 and Jacques Pouyssegur1, 3* 1 Institute for Research on Cancer and Aging (IRCAN), University of Nice, CNRS, INSERM,Centre A. Lacassagne, France 2 Life and Health Sciences Research Institute, University of Minho, Portugal 3 Centre Scientifique de Monaco, Monaco Background and aim. In response to the hypoxic tumor microenvironment, tumor cells shift their metabolism towards glycolysis leading to a high production of lactic acid, which is efficiently exported by the MonoCarboxylate Transporters (MCTs). These MCTs (1 and 4) are H+/lactate symporters that require an interaction with an ancillary protein, CD147/ Basigin, for their plasma membrane expression and function. Basigin is a conserved transmembrane glycoprotein that is strongly expressed in several tumor types. Considering the multiplicity of functions and interactions of CD147/Basigin, its role in promotion of tumour growth has remained poorly defined. Methods. To gain insight into this question, we designed experiments using Zinc Finger Nuclease (ZFN)-mediated basigin and mct4 knockouts in the colon adenocarcinoma (LS174T), the lung carcinoma (A549), and the glioblastoma (U87) human cell lines. Results. First, we demonstrated that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumours via MCT1/4 activity. Second, we showed that basigin gene knockout reduced the plasma membrane expression of MCT1/4 and lactate transport. As a consequence of this decrease, cells accumulated a large pool of intracellular lactate and redirected part of their energy metabolism towards oxidative phosphorylation. This glycolytic/MCT-block ‘escape’ allowed these tumor cells to display residual growth in vitro and in vivo. Thirdly, we found that in contrast to tumour parental cells, their derivatives basigin-/- or basigin-/- and mct4-/- became highly sensitive to phenformin, an inhibitor of mitochondrial complex I. Phenformin addition to these Basigin/MCT disrupted cells in normoxic and hypoxic conditions induced a major drop in cellular ATP provoking growth arrest and cell death via ‘metabolic catastrophe’. Conclusions. These findings highlight that a major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export could provide an efficient anticancer approach, in particular when combined with phenformin. Acknowledgements This work was funded by the Ligue Nationale Contre le Cancer (équipe labélisée), National Cancer Institute and European grant EU7-METOXIA. Keywords: Glycolysis, basigin, monocarboxylate transporters, Oxidative Phosphorylation, ATP, phenformin. Conference: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013. Presentation Type: Abstract Topic: 2. Membrane transporter in intracellular and extracellular pH-control Citation: Marchiq I, Le Floch R, Granja S, Roux D and Pouyssegur J (2014). Inhibition of lactate export by genetic disruption of MCT/basigin complex sensitizes tumor cells to phenformin. Front. Pharmacol. Conference Abstract: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer. doi: 10.3389/conf.fphar.2014.61.00029 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Jan 2014; Published Online: 07 Feb 2014. * Correspondence: Dr. Jacques Pouyssegur, Institute for Research on Cancer and Aging (IRCAN), University of Nice, CNRS, INSERM,Centre A. Lacassagne, Nice, France, Jacques.Pouyssegur@unice.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Ibtissam Marchiq Renaud Le Floch Sara Granja Daniele Roux Jacques Pouyssegur Google Ibtissam Marchiq Renaud Le Floch Sara Granja Daniele Roux Jacques Pouyssegur Google Scholar Ibtissam Marchiq Renaud Le Floch Sara Granja Daniele Roux Jacques Pouyssegur PubMed Ibtissam Marchiq Renaud Le Floch Sara Granja Daniele Roux Jacques Pouyssegur Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.