Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle

• Published in: Molecular metabolism (Germany) Vol. 54; p. 101389
• Main Authors: Duraj, Tomás, Carrión-Navarro, Josefa, Seyfried, Thomas N., García-Romero, Noemí, Ayuso-Sacido, Angel
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01-12-2021; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Animals; Cancer; Cell Proliferation; Energy Metabolism; Glycolysis; Humans; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Oxidative phosphorylation; Research design; Review; Glycolysis; Energy metabolism; Research design; Oxidative phosphorylation; Cancer
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2021.101389

Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for cellular proliferation. Regarding bioenergetics (ATP generation), most cancers display a preference not only toward aerobic glycolysis (“Warburg effect”) and glutaminolysis (mitochondrial substrate level-phosphorylation) but also toward other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands.
The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time.
Standardization of principal readouts might help researchers to collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.
•Normal and cancer cells differ in substrate level phosphorylation and mitochondrial rewiring of ATP-generating pathways.•Glucose and glutamine are two major fuels for tumor growth. Their allocation is dependent on mitochondrial function.•Secondary metabolites assist in proliferation but cannot fully cover ATP demands.•Metabolic therapy is a promising cancer management strategy, but standardization and patient stratification is required.•Bioenergetics can be assessed in vitro using bench top and integrated solutions and in vivo via metabolic imaging.