Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo .

Autor:	Mycielska ME; Department of Surgery, University Hospital Regensburg, Regensburg, Germany. edward.geissler@ukr.de maria.mycielska@ukr.de., Dettmer K; Institute of Functional Genomics, University of Regensburg, Regensburg, Germany., Rümmele P; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany., Schmidt K; Department of Surgery, University Hospital Regensburg, Regensburg, Germany., Prehn C; German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany., Milenkovic VM; Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany., Jagla W; Institut für Pathologie Kaufbeuren-Ravensburg, Kaufbeuren, Germany., Madej GM; Department of Biophysics II, University of Regensburg, Regensburg, Germany., Lantow M; Department of Surgery, University Hospital Regensburg, Regensburg, Germany., Schladt M; Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany., Cecil A; German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany., Koehl GE; Department of Surgery, University Hospital Regensburg, Regensburg, Germany., Eggenhofer E; Department of Surgery, University Hospital Regensburg, Regensburg, Germany., Wachsmuth CJ; Institute of Functional Genomics, University of Regensburg, Regensburg, Germany., Ganapathy V; Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas., Schlitt HJ; Department of Surgery, University Hospital Regensburg, Regensburg, Germany., Kunzelmann K; Physiological Institute, University of Regensburg, Regensburg, Germany., Ziegler C; Department of Biophysics II, University of Regensburg, Regensburg, Germany., Wetzel CH; Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany., Gaumann A; Institut für Pathologie Kaufbeuren-Ravensburg, Kaufbeuren, Germany., Lang SA; Department of Surgery, University Hospital Regensburg, Regensburg, Germany., Adamski J; German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany., Oefner PJ; Institute of Functional Genomics, University of Regensburg, Regensburg, Germany., Geissler EK; Department of Surgery, University Hospital Regensburg, Regensburg, Germany. edward.geissler@ukr.de maria.mycielska@ukr.de.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 May 15; Vol. 78 (10), pp. 2513-2523. Date of Electronic Publication: 2018 Mar 06.
DOI:	10.1158/0008-5472.CAN-17-2959
Abstrakt:	Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy. Significance: Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. Cancer Res; 78(10); 2513-23. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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