Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

Int J Mol Med. 2012 May;29(5):906-12. doi: 10.3892/ijmm.2012.901. Epub 2012 Feb 3.

Abstract

Recent studies have shown that transforming growth factor-β1 (TGF-β1) signaling plays important roles in the redox system in benign and malignant cells. Whether TGF-β mediates an antioxidative damage response in colorectal cancer cells is largely unknown. Herein, using the human colorectal cancer cell lines we found that TGF-β1 induced glutathione peroxidase-1 (GPx-1) expression and enzyme activity, and that the upregulation of GPx-1 by TGF-β1 could protect colorectal cell lines from H2O2-induced oxidation damage. Further, we used loss- and gain-function approaches to elucidate the underlying mechanism and found that TGF-β1 induced GPx-1 through activation of the TGF-β receptor type I (TGF-βRI)/Smad2/extracellular-signal-regulated kinase 1/2 (ERK1/2)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. This cascade could be blocked by the TGF-βRI inhibitor or ERK1/2 inhibitor. Taken together, our data demonstrated that TGF-β1 induced GPx-1 expression and enzymatic activity via the TGF-βRI/Smad2/ERK1/2/HIF-1α signaling pathway, suggesting a novel antioxidative protective function of TGF-β1 in colorectal cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism*
  • Cell Death
  • Cell Line, Tumor
  • Colon / metabolism
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism*
  • Humans
  • Hydrogen Peroxide / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • MAP Kinase Signaling System
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Antioxidants
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta1
  • Hydrogen Peroxide
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase