Abstract
Simple SummaryDepending 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.
Highlights
During transformation, cells reprogram metabolism altering biosynthetic and bioenergetic pathways to guarantee biomass for proliferation, redox control and energy turnover [1,2].In 1924, Otto Warburg described the first and most studied metabolic alteration in malignant cells namely aerobic glycolysis [3,4], in which cancer cells import glucose and export lactate even in the presence of oxygen, supposedly due to dysfunction in oxidative metabolism
To evaluate the succinate transport and uptake across the plasma membrane, metabolomic analysis was performed with cells incubated with 5 mM succinic acid-13C4
Succinate accumulation in prostate tumor cells was found associated to loss of the tumor suppressor phosphatase and tensin-homolog deleted from chromosome ten (PTEN) [37]
Summary
Cells reprogram metabolism altering biosynthetic and bioenergetic pathways to guarantee biomass for proliferation, redox control and energy turnover [1,2].In 1924, Otto Warburg described the first and most studied metabolic alteration in malignant cells namely aerobic glycolysis [3,4], in which cancer cells import glucose and export lactate even in the presence of oxygen, supposedly due to dysfunction in oxidative metabolism (i.e., mitochondrial respiration). Cells reprogram metabolism altering biosynthetic and bioenergetic pathways to guarantee biomass for proliferation, redox control and energy turnover [1,2]. Many studies have shown that mitochondrial function is essential for tumor growth [5], and changes in expression of glucose transporters and glycolytic enzymes are more associated with proliferating cells rather than solely malignant transformation [1]. The tricarboxylic acid (TCA) cycle generates intermediates that support biosynthesis of lipids, amino acids, and nucleotides. These metabolites are necessary for other metabolic pathways, as well as proliferation [6]. Dysregulation in SDH may exert effects on many metabolic pathways [8] and bioenergetics
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