Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells.
Hypoxia inducible factors (HIFs) plays an important role in oxygen compromised environments and therefore in tumour survival. In this research, metabolomics has been applied to study HIFs metabolic function in two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby the metabolism has been profiled for a range of oxygen potentials. Wild type cells have been compared to cells deficient in HIF signalling to reveal its effect on cellular metabolism under normal oxygen conditions as well as low oxygen, hypoxic and anoxic environments. Characteristic responses to hypoxia that were conserved across both cell models involved the anti-correlation between 2-hydroxyglutarate, 2-oxoglutarate, fructose, hexadecanoic acid, hypotaurine, pyruvate and octadecenoic acid with 4-hydroxyproline, aspartate, cysteine, glutamine, lysine, malate and pyroglutamate. Further to this, network-based correlation analysis revealed HIF specific pathway responses to each oxygen condition that were also conserved between cell models. From this, 4-hydroxyproline was revealed as a regulating hub in low oxygen survival of WT cells while fructose appeared to be in HIF deficient cells. Pathways surrounding these hubs were built from the direct connections of correlated metabolites that look beyond traditional pathways in order to understand the mechanism of HIF response to low oxygen environments.
School of Chemical Engineering and Analytical Science, Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
Emily G
EG
Armitage
School of Chemical Engineering and Analytical Science, Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
Helen L
HL
Kotze
School of Chemistry, Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
J William
JW
Allwood
School of Chemistry, Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.|Centre for Endocrinology and Diabetes, Institute of Human Development, The University of Manchester, Manchester M13 9PL, UK.|Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, York Place, off Oxford Road, Manchester M13 9WL, UK.
Warwick B
WB
Dunn
School of Chemistry, Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK.
Royston
R
Goodacre
Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Kaye J
KJ
Williams
D015415:Biomarkers / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055432:Metabolomics / Q000379:methods; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D015415:Biomarkers; D051793:Hypoxia-Inducible Factor 1; D006909:Hydroxyproline; D010100:Oxygen