o:2107 Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT en 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 1552099 10.3389/fonc.2022.976961 2023-09-18T14:55:04.830Z 44 yes 46 Mostafa A. Aboouf University of Zurich / Ain Shams University Franco Guscetti University of Zurich person Nadine von Büren University of Zurich person Julia Armbruster University of Zurich person Hyrije Ademi University of Zurich person Maja Ruetten PathoVet AG person Florinda Meléndez-Rodríguez Autonomous University of Madrid person Thomas Rülicke University of Veterinary Medicine Vienna person 0000-0002-2121-9496 Alexander Seymer Paris Lodron University of Salzburg person Robert A. Jacobs University of Colorado Colorado Springs person Edith M. Schneider Gasser University of Zurich person Julian Aragones Autonomous University of Madrid person Drorit Neumann Tel Aviv University person Max Gassmann University of Zurich person Markus Thiersch University of Zurich person application/pdf 8549776 https://phaidra.vetmeduni.ac.at/o:2107 no yes 16 70 1552253 Frontiers in Oncology 16 12 Frontiers Media Sa 2022