Bastos Sant'Anna Silva 2021 Cancers

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Bastos Sant'Anna Silva AC, Perez Valencia JA, Sciacovelli M, Lalou C, Sarlak S, Tronci L, Nikitopoulou E, Meszaros AT, Frezza C, Rossignol R, Gnaiger E, Klocker H (2021) Succinate anaplerosis has an onco-driving potential in prostate cancer cells. Cancers 13:1727.

» Open Access

Bastos Sant'Anna Silva Ana Carolina, Perez Valencia Juan Alberto, Sciacovelli Marco, Lalou Claude, Sarlak Saharnaz, Tronci Laura, Nikitopoulou Efterpi, Meszaros Andras T, Frezza Christian, Rossignol Rodrigue, Gnaiger Erich, Klocker Helmut (2021) Cancers

Abstract: 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.

Keywords: Cancer metabolism, Prostate cancer, Anaplerosis, Mitochondria, Succinate Bioblast editor: Plangger M O2k-Network Lab: AT Innsbruck Oroboros, AT Innsbruck Schneeberger S, FR Bordeaux Rossignol R, AT Innsbruck Gnaiger E


Labels: MiParea: Respiration  Pathology: Cancer 

Organism: Human  Tissue;cell: Genital  Preparation: Permeabilized cells, Intact cells  Enzyme: Complex IV;cytochrome c oxidase  Regulation: Substrate  Coupling state: LEAK, ROUTINE, OXPHOS  Pathway: S, ROX  HRR: Oxygraph-2k 

2021-04