title: Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling.
abstract: Cadmium has been widely used in industry and is known to be carcinogenic to humans. Although it is widely accepted that chronic exposure to cadmium increases the incidence of cancer, the mechanisms underlying cadmium-induced carcinogenesis are unclear. The main aim of this study was to investigate the role of reactive oxygen species (ROS) in cadmium-induced carcinogenesis and the signal transduction pathways involved. Chronic exposure of human bronchial epithelial BEAS-2B cells to cadmium induced cell transformation, as evidenced by anchorage-independent growth in soft agar and clonogenic assays. Chronic cadmium treatment also increased the potential of these cells to invade and migrate. Injection of cadmium-stimulated cells into nude mice resulted in the formation of tumors. In contrast, the cadmium-mediated increases in colony formation, cell invasion and migration were prevented by transfection with catalase, superoxide dismutase-1 (SOD1), or SOD2. In particular, chronic cadmium exposure led to activation of signaling cascades involving PI3K, AKT, GSK-3β, and β-catenin and transfection with each of the above antioxidant enzymes markedly inhibited cadmium-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the cadmium-mediated increase in total and active β-catenin proteins and colony formation. Moreover, there was a marked induction of AKT, GSK-3β, β-catenin, and carcinogenic markers in tumor tissues formed in mice after injection with cadmium-stimulated cells. Collectively, our findings suggest a direct involvement of ROS in cadmium-induced carcinogenesis and implicate a role of AKT/GSK-3β/β-catenin signaling in this process.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536-0305, USA.
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Pratheeshkumar
authors.initials: P
authors.lastname: Poyil
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Hitron
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000502:physiology*
chemical_list: D002273:Carcinogens; D017382:Reactive Oxygen Species; D051176:beta Catenin; D002104:Cadmium; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3