Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT

Mostafa A Aboouf; Franco Guscetti; Nadine von Büren; Julia Armbruster; Hyrije Ademi; Maja Ruetten; Florinda Meléndez-Rodríguez; Thomas Rülicke; Alexander Seymer; Robert A Jacobs; Edith M Schneider Gasser; Julian Aragones; Drorit Neumann; Max Gassmann; Markus Thiersch

doi:10.3389/fonc.2022.976961

Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT

Front Oncol. 2022 Aug 16:12:976961. doi: 10.3389/fonc.2022.976961. eCollection 2022.

Authors

Mostafa A Aboouf^{1

2

3

4}, Franco Guscetti⁵, Nadine von Büren^{1

3}, Julia Armbruster^{1

3}, Hyrije Ademi^{1

3}, Maja Ruetten⁶, Florinda Meléndez-Rodríguez⁷, Thomas Rülicke⁸, Alexander Seymer⁹, Robert A Jacobs¹⁰, Edith M Schneider Gasser^{1

11}, Julian Aragones⁷, Drorit Neumann¹², Max Gassmann^{1

2}, Markus Thiersch^{1

2

3}

Affiliations

¹ Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
² Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
³ Center for Clinical Studies, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
⁴ Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
⁵ Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
⁶ PathoVet AG, Pathology Diagnostic Laboratory, Tagelswangen, Switzerland.
⁷ Hospital Universitario Santa Cristina, Autonomous University of Madrid, Madrid, Spain.
⁸ Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.
⁹ Department for Sociology and Social Geography, Paris Lodron University of Salzburg (PLUS), Salzburg, Austria.
¹⁰ Department of Human Physiology & Nutrition, University of Colorado Colorado Springs (UCCS), Colorado Springs, CO, United States.
¹¹ Center of Neuroscience Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
¹² Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.

Abstract

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.

Keywords: OXPHOS; VDAC1; erythropoietin receptor; mitochondrial biogenesis; nitric oxide (NO); respirometry; tumor metabolism.