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

Persistent Link:
http://hdl.handle.net/10150/321003
Title:
Arsenic Induced Pseudohypoxia in Malignant Transformation: the Role of HIF-1A Mediated Metabolism Disturbance
Author:
Zhao, Fei
Issue Date:
2014
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
Keywords:
BEAS-2B; Glycolysis; HIF-1A; metabolism; Transformation; Pharmacology & Toxicology; Arsenic
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology & Toxicology
Degree Grantor:
University of Arizona
Advisor:
Klimecki, Walter T.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleArsenic Induced Pseudohypoxia in Malignant Transformation: the Role of HIF-1A Mediated Metabolism Disturbanceen_US
dc.creatorZhao, Feien_US
dc.contributor.authorZhao, Feien_US
dc.date.issued2014-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.description.releaseRelease 23-Apr-2015en_US
dc.description.abstractEpidemiology 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.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectBEAS-2Ben_US
dc.subjectGlycolysisen_US
dc.subjectHIF-1Aen_US
dc.subjectmetabolismen_US
dc.subjectTransformationen_US
dc.subjectPharmacology & Toxicologyen_US
dc.subjectArsenicen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorKlimecki, Walter T.en_US
dc.contributor.committeememberKlimecki, Walter T.en_US
dc.contributor.committeememberLantz, Robert Clarken_US
dc.contributor.committeememberVaillancourt, Richard R.en_US
dc.contributor.committeememberWondrak, Georg T.en_US
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