Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling

Young Ok Son, Lei Wang, Pratheeshkumar Poyil, Amit Budhraja, J. Andrew Hitron, Zhuo Zhang, Jeong Chae Lee, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

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.

Original languageEnglish
Pages (from-to)153-160
Number of pages8
JournalToxicology and Applied Pharmacology
Volume264
Issue number2
DOIs
StatePublished - Oct 15 2012

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health ( R01ES015518 , 1R01CA119028 , and 1R01CA116697 ).

Keywords

  • Cadmium
  • Carcinogenesis
  • GSK-3β
  • ROS
  • β-catenin

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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