Fatty Acid Metabolites in Rapidly Proliferating Breast Cancer

Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2013; 8(5):e63076. DOI: 10.1371/journal.pone.0063076
Source: PubMed


Breast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer's malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer.
We used selective ion monitoring-mass spectrometry to quantify in the cancer and normal breast tissue of 27 patients metabolites that stimulate (15-, 12-, 5-hydroxy-, and 5-oxo-eicosatetraenoate, 13-hydroxy-octadecaenoate [HODE]) or inhibit (prostaglandin [PG]E2 and D2) breast cancer cell proliferation. We then related their levels to each cancer's proliferation rate as defined by its Mib1 score.
13-HODE was the only metabolite strongly, significantly, and positively associated with Mib1 scores. It was similarly associated with aggressive grade and a key component of grade, mitosis, and also trended to be associated with lymph node metastasis. PGE2 and PGD2 trended to be negatively associated with these markers. No other metabolite in cancer and no metabolite in normal tissue had this profile of associations.
Our data fit a model wherein the overproduction of 13-HODE by 15-lipoxygenase-1 shortens breast cancer survival by stimulating its cells to proliferate and possibly metastasize; no other oxygenase-metabolite pathway, including cyclooxygenase-PGE2/D2 pathways, uses this specific mechanism to shorten survival.

Download full-text


Available from: Edward A. Levine,
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput screen (qHTS) to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition, which has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT-22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Finally, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.
    Journal of Medicinal Chemistry 03/2014; 57(10). DOI:10.1021/jm401915r · 5.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bioactive oxidized linoleic acid metabolites (OXLAMs) include 13- and 9-hydroxy-octadecadienoic acid (13-HODE + 9-HODE), and have been linked to oxidative stress, inflammation, and pathological and physiological states. The purpose of this study was to measure changes in plasma 13-HODE + 9-HODE following a 75-km cycling bout and identify potential linkages to linoleate metabolism and established biomarkers of oxidative stress (F2-isoprostanes) and inflammation (cytokines) using a metabolomics approach. Trained male cyclists (N=19, age 38.0±1.6 y, wattsmax 304±10.5) engaged in a 75-km cycling time trial on their own bicycles using electromagnetically-braked cycling ergometers (2.71±0.07 h). Blood samples were collected pre-exercise, and immediately post-, 1.5-h post-, and 21-h post-exercise, and analyzed for plasma cytokines (IL-6, IL-8, IL-10, TNFα, MCP-1, GCSF), F2-isoprostanes, and shifts in metabolites using global metabolomics procedures with GC-MS and LC-MS. 13-HODE + 9-HODE increased 3.1-fold and 1.7-fold immediately post- and 1.5-h post-exercise (both p<0.001), and returned to pre-exercise levels by 21-h post-exercise. Post-75-km cycling plasma levels of 13-HODE + 9-HODE were not significantly correlated with increases in plasma cytokines, but were positively correlated with post-exercise F2-isoprostanes (r=0.75, p<0.001), linoleate (r=0.54, P=0.016), arachidate (r=0.77, p<0.001), 12,13-dihydroxy-9Z-octadecenoate (12,13-DiHOME) (r=0.60, p=0.006), dihomo-linolenate (r=0.57, p=0.011), and adrenate (r=0.56, p=0.013). These findings indicate that prolonged and intensive exercise caused a transient, 3.1-fold increase in the stable linoleic acid oxidation product 13-HODE + 9-HODE, and was related to increases in F2-isoprostanes, linoleate, and fatty acids in the linoleate conversion pathway. These data support the use of 13-HODE + 9-HODE as an oxidative stress biomarker in acute exercise investigations.
    AJP Regulatory Integrative and Comparative Physiology 04/2014; 307(1). DOI:10.1152/ajpregu.00092.2014 · 3.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The importance of lipids in health and disease has been widely acknowledged. Lipids are well known to undergo enzymatic and/or non-enzymatic conversions to lipid mediators (LMs), which demonstrate potent actions in various biological events, such as the regulation of cellular signaling pathways and the promotion and resolution of inflammation. LMs activate G-protein-coupled receptors (GPCRs) to exert various functions. Monitoring these mediators in disease is essential to uncover the mechanisms of pathogenesis for many diseases, such as asthma, rheumatoid arthritis, Alzheimer's disease, and cancer. Along with technical developments in mass spectrometry, highly sensitive and multiplexed analyses of LMs in the human periphery and other tissues have become available. These advancements enable the temporal and spatial profiling of LMs; therefore, the findings obtained from LM profiling are expected to decode pathology. As trace amounts of LMs can exert functions, the development of a highly sensitive, accurate, and robust analytical method is necessary. Although not mandatory, mediator lipidomics validation is becoming popular and remains challenging. Because LMs already exist in biological matrices, evaluations of the matrix effect and extraction efficiencies are important issues. Thus, more careful analyses are required. In this review, we focus on mediator lipidomics, including polyunsaturated fatty acids (PUFAs), such as omega-3 and omega-6 fatty acids, and LMs derived from PUFAs, such as eicosanoids, lipoxins and resolvins. In addition to the recent progress in human mediator lipidomics, bioanalytical insights derived from this field (i.e., effective sample preparation from biological matrices and evaluation of the matrix effect) are described herein.
    Journal of Pharmaceutical and Biomedical Analysis 02/2015; 113:151-162. DOI:10.1016/j.jpba.2015.02.011 · 2.98 Impact Factor
Show more