1. Academic Validation
  2. Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine

Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine

  • Cancer Lett. 2022 Feb 1;526:91-102. doi: 10.1016/j.canlet.2021.11.024.
Philipp Rabe 1 Aenne-Dorothea Liebing 1 Petra Krumbholz 1 Robert Kraft 2 Claudia Stäubert 3
Affiliations

Affiliations

  • 1 Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany.
  • 2 Carl Ludwig Institute for Physiology, Faculty of Medicine, Leipzig University, Liebigstraße 27, 04103, Leipzig, Germany.
  • 3 Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany. Electronic address: claudia.staeubert@medizin.uni-leipzig.de.
Abstract

Cancer cells display metabolic alterations to meet the bioenergetic demands for their high proliferation rates. Succinate is a central metabolite of the tricarboxylic acid (TCA) cycle, but was also shown to act as an oncometabolite and to specifically activate the Succinate Receptor 1 (SUCNR1), which is expressed in several types of Cancer. However, functional studies focusing on the connection between SUCNR1 and Cancer cell metabolism are still lacking. In the present study, we analyzed the role of SUCNR1 for Cancer cell metabolism and survival applying different signal transduction, metabolic and imaging analyses. We chose a gastric, a lung and a pancreatic Cancer cell line for which our data revealed functional expression of SUCNR1. Further, presence of glutamine (Gln) caused high respiratory rates and elevated expression of SUCNR1. Knockdown of SUCNR1 resulted in a significant increase of mitochondrial respiration and superoxide production accompanied by an increase in TCA cycle throughput and a reduction of Cancer cell survival in the analyzed Cancer cell lines. Combination of SUCNR1 knockdown and treatment with the chemotherapeutics cisplatin and gemcitabine further increased Cancer cell death. In summary, our data implicates that SUCNR1 is crucial for Gln-addicted Cancer cells by limiting TCA cycle throughput, mitochondrial respiration and the production of Reactive Oxygen Species, highlighting its potential as a pharmacological target for Cancer treatment.

Keywords

Cancer metabolism; GPR91; Glutaminolysis; Metabolite-sensing GPCR; SUCNR1.

Figures
Products