journal contribution posted on 2023-03-31, 02:02 authored by Maria E. Mycielska, Katja Dettmer, Petra Rümmele, Katharina Schmidt, Cornelia Prehn, Vladimir M. Milenkovic, Wolfgang Jagla, Gregor M. Madej, Margareta Lantow, Moritz Schladt, Alexander Cecil, Gudrun E. Koehl, Elke Eggenhofer, Christian J. Wachsmuth, Vadivel Ganapathy, Hans J. Schlitt, Karl Kunzelmann, Christine Ziegler, Christian H. Wetzel, Andreas Gaumann, Sven A. Lang, Jerzy Adamski, Peter J. Oefner, Edward K. Geissler
Cancer cell proliferation in the presence of extracellular citrate.
German Federal Ministry of Education and Research
Bavarian Government to Women in Research and Education
ARTICLE ABSTRACTGlycolysis 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.