Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo
Mycielska ME, Dettmer K, Ruemmele P, Schmidt K, Prehn C, Milenkovic VM, Jagla W, Madej GM, Lantow M, Schladt M, Cecil A, Koehl GE, Eggenhofer E, Wachsmuth CJ, Ganapathy V, Schlitt HJ, Kunzelmann K, Ziegler C, Wetzel CH, Gaumann A, Lang SA, Adamski J, Oefner PJ, Geissler EK (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 78
Pages Range: 2513-2523
Journal Issue: 10
DOI: 10.1158/0008-5472.CAN-17-2959
Abstract
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.
Involved external institutions
Universität Regensburg
Germany (DE)
Universitätsklinikum Regensburg
Germany (DE)
Texas Tech University (TTU)
United States (USA) (US)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Institut für Pathologie Kaufbeuren-Ravensburg GbR
Germany (DE)
Germany (DE)
Universitätsklinikum Regensburg
Germany (DE)
Texas Tech University (TTU)
United States (USA) (US)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Institut für Pathologie Kaufbeuren-Ravensburg GbR
Germany (DE)
How to cite
APA:
Mycielska, M.E., Dettmer, K., Ruemmele, P., Schmidt, K., Prehn, C., Milenkovic, V.M.,... Geissler, E.K. (2018). Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo. Cancer Research, 78(10), 2513-2523. https://dx.doi.org/10.1158/0008-5472.CAN-17-2959
MLA:
Mycielska, Maria E., et al. "Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo." Cancer Research 78.10 (2018): 2513-2523.
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