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

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.

Plasma Metabolomics for Discovery of Early Metabolic Markers of Prostate Cancer Based on Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry

“…Untargeted metabolomics is a "hypothesis-generating discovery strategy" that compares different groups of samples (e.g., cancer vs. controls) [26], which is a promising approach to identify novel metabolic markers. This strategy has been applied recently in PCa [19,27]. Thus, the combination of ultra-high-performance liquid chromatography with high-resolution mass spectrometry (UHPLC-HRMS) and epidemiological approaches may open new perspectives in PCa research, enabling the identification of novel biomarkers for evaluating the future risk of PCa, and the investigation of the etiology of PCa [28][29][30].…”

The involvement of high succinylation modification in the development of prostate cancer

“…It has been reported that abnormal metabolism of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of PCa cells ( 12 ). Succinate is the most important substrate for lysine succinylation modification.…”

Valine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate Cancer

“…Over the past few years, enhanced succinate oxidation by SDH has been identified as an emergent hallmark of PCa metabolism [9][10][11] . Increased reliance on succinate in response to reduced Complex I (CI) activity is also not unique to cancer, as cell-permeable succinate has been shown to overcome CI dysfunction in models of mitochondrial disease 34 .…”