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Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases

Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells

Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, 6020 Innsbruck, Austria
Oroboros Instruments GmbH, 6020 Innsbruck, Austria
Institute of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria
Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK
Institut National de la Santé Et de la Recherche Médicale (INSERM) U1211, Bordeaux University, 33076 Bordeaux, France
Department of Surgery, Division of Experimental Urology, University Hospital for Urology, Medical University Innsbruck, 6020 Innsbruck, Austria
Authors to whom correspondence should be addressed.
Academic Editors: Barbara Kofler and Marie Arsenian-Henriksson
Cancers 2021, 13(7), 1727;
Received: 25 February 2021 / Revised: 23 March 2021 / Accepted: 2 April 2021 / Published: 6 April 2021
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
Depending on the availability of nutrients and increased metabolic demands, tumor cells rearrange their metabolism to survive and, ultimately, proliferate. Here, the authors investigated the effect of succinate, a metabolite of the mitochondrial citric acid cycle, on malignant and non-malignant prostate cells. They analyzed uptake through membrane transporters and intracellular accumulation, which subsequently fuels metabolism and enhances oncogenic properties of the tumor cells. The findings shed light to the metabolic adaptations that prostate tumor cells undergo, providing a better understanding of metabolic rewiring and strategies for therapeutic intervention.
Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells. View Full-Text
Keywords: cancer metabolism; prostate cancer; anaplerosis; mitochondria; succinate cancer metabolism; prostate cancer; anaplerosis; mitochondria; succinate
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MDPI and ACS Style

Sant’Anna-Silva, A.C.B.; Perez-Valencia, J.A.; Sciacovelli, M.; Lalou, C.; Sarlak, S.; Tronci, L.; Nikitopoulou, E.; Meszaros, A.T.; Frezza, C.; Rossignol, R.; Gnaiger, E.; Klocker, H. Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells. Cancers 2021, 13, 1727.

AMA Style

Sant’Anna-Silva ACB, Perez-Valencia JA, Sciacovelli M, Lalou C, Sarlak S, Tronci L, Nikitopoulou E, Meszaros AT, Frezza C, Rossignol R, Gnaiger E, Klocker H. Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells. Cancers. 2021; 13(7):1727.

Chicago/Turabian Style

Sant’Anna-Silva, Ana Carolina B., Juan A. Perez-Valencia, Marco Sciacovelli, Claude Lalou, Saharnaz Sarlak, Laura Tronci, Efterpi Nikitopoulou, Andras T. Meszaros, Christian Frezza, Rodrigue Rossignol, Erich Gnaiger, and Helmut Klocker. 2021. "Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells" Cancers 13, no. 7: 1727.

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