Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver

Laughter, Ashley; Dunn, Corrie; Swanson, Cynthia; Howroyd, Paul; Cattley, Russell C.; Corton, J. Christopher

doi:10.1016/j.tox.2004.06.014

Cited by 46 publications

(48 citation statements)

References 51 publications

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“…1J). In addition to being a weak inhibitor of PDK, DCA also blocks glutathione S-transferase (21), inhibits cholesterol biosynthesis (22), promotes oxidative stress (23), and activates peroxisome proliferator-activated receptors (24). Both these published observations and our data persuaded us to use more specific strategies for implicating a role for PDH␣ phosphorylation in cancer biology.…”

Section: Resultsmentioning

confidence: 59%

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

McFate

Mohyeldin

et al. 2008

Journal of Biological Chemistry

340

273

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High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase ␣ (PDH␣) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1␣ (HIF-1␣) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDH␣ phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1␣ expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.Cancer is a disease whereby genetic mutation results in uncontrolled cell growth combined with malignancy. High lactate accumulation, despite adequate oxygen availability, is a metabolic pattern commonly associated with malignant transformation of the uncontrolled dividing cell. This metabolic phenotype, termed aerobic glycolysis and historically known as the Warburg effect, is characterized by high glycolytic rates and reduced mitochondrial oxidation (1, 2), features that may favor cell survival in the hypoxic microenvironments found in tumors. This phenotype also favors the routing of key metabolic intermediates away from oxidative destruction and toward anabolic processes required by rapidly dividing cells (2). Hypoxia and growth factors may select for this phenotype by activating hypoxia-inducible transcription factor-1 (HIF-1), 3 which induces transcription of glucose transporters, glycolytic enzymes, and many other genes associated with hypoxic survival, angiogenesis, and tissue invasion (3). Hypoxia, HIF-1 activation, and high lactate levels in tumors are all independently correlated with poor clinical outcome for many human cancers (3-5). A causative role for hypoxia and HIF-1 stabilization in tumor formation and progression has been demonstrated (reviewed in Ref. 3). However, the buildup of glycoly...

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Section: Resultsmentioning

confidence: 59%

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

McFate

Mohyeldin

et al. 2008

Journal of Biological Chemistry

340

273

View full text Add to dashboard Cite

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“…Elevated liver weights have been reported in untreated PPARa-null or humanized mice [111,139,164,200]. PPARa-null mice have also been reported to have decreased longevity and enhancement of age-dependent lesions and carry a background of chronic diseases (e.g., obesity and steatosis).…”

Section: Tumor Phenotype and Alterations In Oncogenes And Suppressor mentioning

confidence: 99%

DEHP: Genotoxicity and potential carcinogenic mechanisms—A review

Caldwell

2012

Mutation Research/Reviews in Mutation Research

193

101

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“…This compound is commonly found as a pollutant in groundwater, and has been shown to induce concentration-dependent decreases in growth and differentiation of rat embryos, and a corresponding increase in morphological abnormalities (Saillenfait et al, 1995). Although TCE is a known carcinogen in rodents models, most likely mediated via peroxisome proliferation (Laughter et al, 2004), the classification of the compound as a human carcinogen is controversial (Green, 2001). Recently it has been reported that TCE can induce oxidative damage to both DNA in rat liver (Toraason et al, 1999) and to proteins and lipids within rat sperm (DuTeaux et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

NMR-derived developmental metabolic trajectories: an approach for visualizing the toxic actions of trichloroethylene during embryogenesis

et al. 2005

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Fish embryo toxicity tests for chemical risk assessment have traditionally been based upon non-specific endpoints including morphological abnormalities, hatching success, and mortality. Here we extend the application of 1 H NMR-based metabolomics in environmental toxicology by adding a suite of metabolic endpoints to the Japanese medaka (Oryzias latipes) embryo assay, with the goal to provide more sensitive, specific and unbiased biomarkers of toxicity. Medaka were exposed throughout embryogenesis to five concentrations of trichloroethylene (TCE; 0, 8.76, 21.9, 43.8, 87.6, 175 mg/L) and the relative sensitivities of the traditional and metabolomic endpoints compared. While the no-observable-adverse-effect-level for hatching success, the most sensitive traditional indicator, was 164 mg/L TCE, metabolic perturbations were detected at all exposure concentrations. Principal components analysis (PCA) highlighted a dose-response relationship between the NMR spectra of medaka extracts. In addition, 12 metabolites that exhibited highly significant dose-response relationships were identified, which indicated an energetic cost to TCE exposure. Next, embryos were exposed to 0, 0.88, 8.76 mg/L TCE and sampled on each of the 8 days of development. Projections of 66 twodimensional J-resolved NMR spectra were obtained, and PCA revealed developmental metabolic trajectories that characterized the basal and TCE-perturbed changes in the entire NMR-visible metabolome throughout embryogenesis. Although no significant increases in mortality, gross deformity or developmental retardation were observed relative to the control group, TCE-induced metabolic perturbations were observed on day 8. In conclusion, these results support the continued development of NMR-based metabolomics as a rapid and reproducible tool for biomarker discovery and environmental risk assessment.

show abstract

Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver

Cited by 46 publications

References 51 publications

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

DEHP: Genotoxicity and potential carcinogenic mechanisms—A review

NMR-derived developmental metabolic trajectories: an approach for visualizing the toxic actions of trichloroethylene during embryogenesis

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