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    Arsenic Induced Pseudohypoxia in Malignant Transformation: the Role of HIF-1A Mediated Metabolism Disturbance

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    Author
    Zhao, Fei
    Issue Date
    2014
    Keywords
    BEAS-2B
    Glycolysis
    HIF-1A
    metabolism
    Transformation
    Pharmacology & Toxicology
    Arsenic
    Advisor
    Klimecki, Walter T.
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release 23-Apr-2015
    Abstract
    Epidemiology studies have established a strong link between chronic arsenic exposure and lung cancer. Currently, contribution of perturbed energy metabolism to carcinogenesis is an intensive area of research. In several human cell culture models (primary, immortal, malignant), we observed that non-cytotoxic exposure to arsenite increased extracellular acidification rate. Lactate accumulation caused by extracellular acidification, could be inhibited by 2-deoxy-D-glucose, a non-metabolized glucose analog. This established that arsenite induces aerobic glycolysis (the Warburg effect), a metabolic shift frequently observed in the acquisition of malignancy. Our studies in BEAS-2B, a non-malignant pulmonary epithelial cell line, found that the metabolic perturbation began early in the course of malignant transformation by arsenite (6 weeks). Correlated with the surge of glycolysis, we found elevated levels of HIF-1A and loss of E-Cadherin during chronic arsenite exposure. Our evidence suggests that this metabolic shift is sustained by HIF-1A (hypoxia-inducible factor 1A). We found that arsenite-exposed BEAS-2B accumulated HIF-1A protein, and underwent transcriptional up-regulation of HIF-1A-target genes. Overexpression of HIF-1A increases glycolysis 15% (vs. control), confirming that HIF-1A can modulate glycolysis in BEAS-2B. Coincident with induction of glycolysis, we observed a decrease in E-cadherin expression, indicating loss of epithelial identity. HIF-1A stable knockdown in BEAS-2B abrogated the arsenite induction of glycolysis, and indicated suppression in colony formation. These findings suggest that the hypoxia-mimetic effect of arsenite plays an important role in arsenite-induced malignant transformation. The significance of this study is that arsenite-induced alteration of energy metabolism represents the type of fundamental perturbation that could extend to many diverse effects caused by arsenic.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Pharmacology & Toxicology
    Degree Grantor
    University of Arizona
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