Oncosecretomics coupled to bioenergetics identifies α-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes.

Abstract

Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed. Meanwhile, methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors. Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable. This profile changes with microenvironmental conditions (eg. substrate availability), the oncogenes activated (and the tumor suppressors inactivated) and the interaction with the stroma (i.e. reverse Warburg effect). Here, we assessed the power of metabolic footprinting (MFP) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes, c-Myc, KLF4 and Oct1. The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells. We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion. To investigate the potential oncogene-mediated alterations in mitochondrial metabolism, we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release. Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration. KLF4 deficiency also stimulated glycolysis, albeit without cellular respiration impairment. In contrast, Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency. MFP revealed that c-Myc, KLF4 and Oct1 altered amino acid metabolism with specific patterns. We identified isoleucine, α-aminoadipic acid and GABA (γ-aminoisobutyric acid) as biomarkers related. Our findings establish the impact of Oct1, KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile.

• Authors: Nadège Bellance, Lisa Pabst, Genevara Allen, Rodrigue Rossignol, Deepak Nagrath
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1817 Issue 11 Pg. 2060-71 (Nov 2012) ISSN: 0006-3002 [Print] Netherlands
• PMID: 22842522 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• KLF4 protein, human
• Klf4 protein, mouse
• Klf4 protein, rat
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Octamer Transcription Factor-1
• Proto-Oncogene Proteins c-myb
• Isoleucine
• 2-Aminoadipic Acid
• gamma-Aminobutyric Acid

Topics

• 2-Aminoadipic Acid (analysis)
• Animals
• Biomarkers, Tumor (analysis)
• Cells, Cultured
• Energy Metabolism
• Isoleucine (analysis)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (physiology)
• Metabolomics
• Mice
• Neoplasms (metabolism)
• Octamer Transcription Factor-1 (physiology)
• Proto-Oncogene Proteins c-myb (physiology)
• Rats
• gamma-Aminobutyric Acid (analysis)