title: Arsenite-induced pseudo-hypoxia results in loss of anchorage-dependent growth in BEAS-2B pulmonary epithelial cells.
abstract: Epidemiology studies have established a strong link between lung cancer and arsenic exposure. Currently, the role of disturbed cellular energy metabolism in carcinogenesis is a focus of scientific interest. Hypoxia inducible factor-1 alpha (HIF-1A) is a key regulator of energy metabolism, and it has been found to accumulate during arsenite exposure under oxygen-replete conditions. We modeled arsenic-exposed human pulmonary epithelial cells in vitro with BEAS-2B, a non-malignant lung epithelial cell line. Constant exposure to 1 µM arsenite (As) resulted in the early loss of anchorage-dependent growth, measured by soft agar colony formation, beginning at 6 weeks of exposure. This arsenite exposure resulted in HIF-1A accumulation and increased glycolysis, similar to the physiologic response to hypoxia, but in this case under oxygen-replete conditions. This "pseudo-hypoxia" response was necessary for the maximal acquisition of anchorage-independent growth in arsenite-exposed BEAS-2B. The HIF-1A accumulation and induction in glycolysis was sustained throughout a 52 week course of arsenite exposure in BEAS-2B. There was a time-dependent increase in anchorage-independent growth during the exposure to arsenite. When HIF-1A expression was stably suppressed, arsenite-induced glycolysis was abrogated, and the anchorage-independent growth was reduced. These findings establish that arsenite exerts a hypoxia-mimetic effect, which plays an important role in the subsequent gain of malignancy-associated phenotypes.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Malm
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Hinchman
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Connor G
authors.initials: CG
authors.lastname: Beeks
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D018053:Arsenites / Q000633:toxicity*; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D004734:Energy Metabolism / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D008401:Gas Chromatography-Mass Spectrometry; D006019:Glycolysis / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D019344:Lactic Acid / Q000378:metabolism; D055432:Metabolomics; D009841:Oligonucleotides; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018053:Arsenites; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009841:Oligonucleotides; D019344:Lactic Acid; C015001:arsenite