Succinate-Directed Approaches for Warburg Effect-Targeted Cancer Management, an Alternative to Current Treatments?

Abstract

Approximately a century ago, Otto Warburg discovered that cancer cells use a fermentative rather than oxidative metabolism even though the former is more inefficient in terms of energy production per molecule of glucose. Cancer cells increase the use of this fermentative metabolism even in the presence of oxygen, and this process is called aerobic glycolysis or the Warburg effect. This alternative metabolism is mainly characterized by higher glycolytic rates, which allow cancer cells to obtain higher amounts of total ATP, and the production of lactate, but there are also an activation of protumoral signaling pathways and the generation of molecules that favor cancer progression. One of these molecules is succinate, a Krebs cycle intermediate whose concentration is increased in cancer and which is considered an oncometabolite. Several protumoral actions have been associated to succinate and its role in several cancer types has been already described. Despite playing a major role in metabolism and cancer, so far, the potential of succinate as a target in cancer prevention and treatment has remained mostly unexplored, as most previous Warburg-directed anticancer strategies have focused on other intermediates. In this review, we aim to summarize succinate’s protumoral functions and discuss the use of succinate expression regulators as a potential cancer therapy strategy.

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“…Authors concluded that mutation in the amino acid sequence of SDHB rewires metabolism, resembling metabolic reprogramming in cancer [ 60 ]. Similar observations have been reported by other scientists who showed strong evidence that some mutations in SDH impair oxidative phosphorylation, which highly contributes to the Warburg metabolism switch observed in cancer cells [ 61 – 63 ]. The advantage of the Warburg phenomenon in cancer cells has been unclear however it was proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new progeny of cells.…”

uL3 Regulates Redox Metabolism and Ferroptosis Sensitivity of p53-Deleted Colorectal Cancer Cells

“…In cancer cells, glutamine is converted into tricarboxylic acid cycle metabolites to maintain mitochondrial function in condition of aerobic glycolysis [59]. According to the metabolic hallmarks of malignant progression and aggressiveness in several cancers [60], we also found abnormal choline metabolism and high levels of succinate and fumarate in resistant cells compared to sensitive ones (Figure 2a,b).…”

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“…The SDH assembly factor (SDHAF) is required for the flavination of SDHA, which is required for the formation of the SDH complex [ 67 ]. The 16 exons of the SDHA gene are located on chromosome 5p15.33 [ 10 , 22 ]. The succinate binding site is a component of SDHA, which is the main catalytic element that converts succinate to fumarate.…”