Aboouf Mostafa A, Guscetti Franco, von Büren Nadine, Armbruster Julia, Ademi Hyrije, Ruetten Maja, Meléndez-Rodríguez Florinda, Rülicke Thomas, Seymer Alexander, Jacobs Robert A, Schneider Gasser Edith M, Aragones Julian, Neumann Drorit, Gassmann Max, Thiersch Markus
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Front Oncol. 2022 Aug 16;12:976961. doi: 10.3389/fonc.2022.976961. eCollection 2022.
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 high-resolution respirometry. Furthermore, we analyzed cellular respiratory control, mitochondrial content, and regulators of mitochondrial biogenesis and 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.
促红细胞生成素受体（EPOR）在健康组织和恶性组织中广泛表达。在某些恶性肿瘤中，EPOR会刺激肿瘤生长。在健康组织中，EPOR控制除红细胞生成以外的其他过程，包括线粒体代谢。我们推测EPOR也控制癌细胞中的线粒体代谢。为了验证这一假设，我们构建了EPOR敲低的癌细胞，使其在小鼠体内生长肿瘤异种移植物，并通过高分辨率呼吸测定法分析肿瘤细胞呼吸。此外，我们分析了不同癌细胞系中的细胞呼吸控制、线粒体含量以及线粒体生物发生的调节因子。我们的结果表明，EPOR通过控制pAKT和诱导型一氧化氮合酶（iNOS）的水平来控制肿瘤生长和肿瘤中的线粒体生物发生。此外，我们观察到在肺癌患者的组织阵列中，EPOR的表达与线粒体标志物电压依赖性阴离子通道1（VDAC1）的表达相关，这表明EPOR确实有助于调节癌症患者肿瘤中的线粒体生物发生。因此，我们的数据表明，EPOR不仅刺激肿瘤生长，还调节肿瘤代谢，并且是针对肿瘤进展进行直接干预的一个靶点。
