Metabolic Reprogramming in Cancer Is Induced to Increase Proton Production

2020/01/13 by Huiyan Sun, Yi Zhou, Michael Skaro +6 · 25 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · #ATP Synthase and ATPases Research #Biochemistry #Biology #Cancer #Cancer cell #Cancer research #Cancer, Hypoxia, and Metabolism #Cell #Cell biology #Chemistry #Gene #Genetics #Intracellular #Mitochondrial Function and Pathology #Nucleotide #Reprogramming #Sialic acid #Warburg effect

paper · pdf · doi:10.1158/0008-5472.can-19-3392

openalex publication_date 2020/01/13 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/03

Abstract

Abstract Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RM) including the Warburg effect, nucleotide de novo synthesis, and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H+ than their original metabolisms. These data strongly support a model that these RMs are induced or selected to neutralize a persistent intracellular alkaline stress due to chronic inflammation and local iron overload. To sustain these RMs for survival, cells must find metabolic exits for the nonproton products of these RMs in a continuous manner, some of which pose major challenges, such as nucleotides and sialic acids, because they are electrically charged. This analysis strongly suggests that continuous cell division and other cancerous behaviors are ways for the affected cells to remove such products in a timely and sustained manner. As supporting evidence, this model can offer simple and natural explanations to a range of long-standing open questions in cancer research including the cause of the Warburg effect. Significance: Inhibiting acidifying metabolic reprogramming could be a novel strategy for treating cancer.

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