Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

Xin Wang, Ardhendu K. Mandal, Hiroshi Saito, Joseph F. Pulliam, Eun Y. Lee, Zun Ji Ke, Jian Lu, Songze Ding, Li Li, Brent J. Shelton, Thomas Tucker, B. Mark Evers, Zhuo Zhang, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway.

Original languageEnglish
Pages (from-to)11-21
Number of pages11
JournalToxicology and Applied Pharmacology
Volume262
Issue number1
DOIs
StatePublished - Jul 1 2012

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants (Xianglin Shi: 1R01CA119028, 1R01CA116697, R01 ES015375, and 1R01ES015518; Hiroshi Saito: R01AG025908).

Keywords

  • 2D-DIGE
  • As(III)
  • Colorectal cancer
  • Cr(VI)
  • ROS
  • Tumorigenesis
  • Wnt/β-catenin pathway

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint

Dive into the research topics of 'Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway'. Together they form a unique fingerprint.

Cite this