1H NMR metabolomics identification of markers of hypoxia-induced metabolic shifts in a breast cancer model system

Abstract

Hypoxia can promote invasive behavior in cancer cells and alters the response to therapeutic intervention as a result of changes in the expression many genes, including genes involved in intermediary metabolism. Although metabolomics technologies are capable of simultaneously measuring a wide range of metabolites in an untargeted manner, these methods have been relatively under utilized in the study of cancer cell responses to hypoxia. Thus, (1)H NMR metabolomics was used to examine the effects of hypoxia in the MDA-MB-231 human breast cancer cell line, both in vitro and in vivo. Cell cultures were compared with respect to their metabolic responses during growth under either hypoxic (1% O(2)) or normoxic conditions. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify a set of metabolites that were responsive to hypoxia. Via intracardiac administration, MDA-MB-231 cells were also used to generate widespread metastatic disease in immuno-compromised mice. Serum metabolite analysis was conducted to compare animals with and without a large tumor burden. Intriguingly, using a cross-plot of the OPLS loadings, both the in vitro and in vivo samples yielded a subset of metabolites that were significantly altered by hypoxia. These included primarily energy metabolites and amino acids, indicative of known alterations in energy metabolism, and possibly protein synthesis or catabolism. The results suggest that the metabolite pattern identified might prove useful as a marker for intra-tumoral hypoxia.

Metabonomics studies on serum and urine of patients with breast cancer using 1H-NMR spectroscopy

“…Therefore, the occurrence and development of tumor are closely related to metabolic changes in the body [16]. Although metabolomics studies have been widely used in a variety of tumors, there are few reports using metabonomics to study biomarkers of breast cancer [17].…”

Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism

“…For instance, glutamate acts as a neurotransmitter in various oxidative stress-related neurodegenerative conditions and has been linked to the development of lung injury in animal models of hyperoxia and sepsis (10,30,36). In addition, threonine levels increase in response to hypoxic injury (42), and elevated levels of tyramine have been reported following myocardial infarction, acute cystitis, and smoking (22,27,43). Further experimental work and bioinformatics analysis is required to determine the precise role of these metabolites in ischemia, oxidative stress, and inflammation.…”

1H NMR metabolomics combined with gene expression analysis for the determination of major metabolic differences between subtypes of breast cell lines

“…[1][2][3] Tumourigenesis and progression is initiated, or at least accompanied, by a number of metabolic changes, some of which facilitate the processes of local invasion and metastasis to distant organs. 4 The majority of cancers exhibit the ''Warburg phenomenon'' where cells demonstrate increased glycolysis leading to enhanced lactate production. [1][2][3] In addition, many authors have reported changes in choline and phosphocholine (PCho) levels in cancers.…”