https://phaidra.vetmeduni.ac.at/o:2107 Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT Aboouf, Mostafa A. Mostafa A. Aboouf University of Zurich / Ain Shams University Thiersch, Markus Markus Thiersch University of Zurich Gassmann, Max Max Gassmann University of Zurich Neumann, Drorit Drorit Neumann Tel Aviv University Aragones, Julian Julian Aragones Autonomous University of Madrid Schneider Gasser, Edith M. Edith M. Schneider Gasser University of Zurich Jacobs, Robert A. Robert A. Jacobs University of Colorado Colorado Springs Rülicke, Thomas Thomas Rülicke 0000-0002-2121-9496 University of Veterinary Medicine Vienna Seymer, Alexander Alexander Seymer Paris Lodron University of Salzburg Meléndez-Rodríguez, Florinda Florinda Meléndez-Rodríguez Autonomous University of Madrid Ruetten, Maja Maja Ruetten PathoVet AG Ademi, Hyrije Hyrije Ademi University of Zurich Armbruster, Julia Julia Armbruster University of Zurich Guscetti, Franco Franco Guscetti University of Zurich von Büren, Nadine Nadine von Büren University of Zurich Frontiers Media Sa text eng Erythropoietin receptor (EPOR) is widely expressed in healthy and malignant tissues. In certain malignancies, EPOR stimulates tumor growth. In healthy tissues, EPOR controls processes other than erythropoiesis, including mitochondrial metabolism. We hypothesized that EPOR also controls the mitochondrial metabolism in cancer cells. To test this hypothesis, we generated EPOR-knockdown cancer cells to grow tumor xenografts in mice and analyzed tumor cellular respiration via high-resolution respirometry. Furthermore, we analyzed cellular respiratory control, mitochondrial content, and regulators of mitochondrial biogenesis in vivo and in vitro in different cancer cell lines. Our results show that EPOR controls tumor growth and mitochondrial biogenesis in tumors by controlling the levels of both, pAKT and inducible NO synthase (iNOS). Furthermore, we observed that the expression of EPOR is associated with the expression of the mitochondrial marker VDAC1 in tissue arrays of lung cancer patients, suggesting that EPOR indeed helps to regulate mitochondrial biogenesis in tumors of cancer patients. Thus, our data imply that EPOR not only stimulates tumor growth but also regulates tumor metabolism and is a target for direct intervention against progression. Nitric-Oxide; Skeletal-Muscle; Gene-Expression; Survival; Growth; Cells; Proliferation; Transcription; Pgc-1-Alpha; Metabolism http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:2107/download 10.3389/fonc.2022.976961 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Frontiers in Oncology 12 (2022) Frontiers in Oncology 12 8.15 MB 2022