Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells

Breast Cancer Res. 2012 Jan 6;14(1):R4. doi: 10.1186/bcr3085.

Abstract

Introduction: The expression of proinflammatory protein tissue transglutaminase 2 (TG2) is frequently upregulated in multiple cancer cell types. However, the exact role of TG2 in cancer cells is not well-understood. We recently initiated studies to determine the significance of TG2 in cancer cells and observed that sustained expression of TG2 resulted in epithelial-to-mesenchymal transition (EMT) and promoted cancer stem cell (CSC) traits in mammary epithelial cells. These results suggested that TG2 could serve as a promising therapeutic target for overcoming chemoresistance and inhibiting metastatic spread of cancer cells.

Methods: Using various mutant constructs, we analyzed the activity of TG2 that is essential for promoting the EMT-CSC phenotype.

Results: Our results suggest that catalytically inactive TG2 (TG2-C277S) is as effective as wild-type TG2 (TG2-WT) in inducing the EMT-CSC in mammary epithelial cells. In contrast, overexpression of a GTP-binding-deficient mutant (TG2-R580A) was completely incompetent in this regard. Moreover, TG2-dependent activation of the proinflammatory transcription factor NF-κB is deemed essential for promoting the EMT-CSC phenotype in mammary epithelial cells.

Conclusions: Our results suggest that the transamidation activity of TG2 is not essential for promoting its oncogenic functions and provide a strong rationale for developing small-molecule inhibitors to block GTP-binding pockets of TG2. Such inhibitors may have great potential for inhibiting the TG2-regulated pathways, reversing drug resistance and inhibiting the metastasis of cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Catalytic Domain
  • Cell Movement
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Drug Resistance, Neoplasm
  • Epithelial Cells / enzymology
  • Epithelial Cells / physiology*
  • Epithelial-Mesenchymal Transition*
  • Female
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism
  • GTP-Binding Proteins / physiology*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Guanosine Triphosphate / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mammary Glands, Human / pathology*
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / physiology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phenotype
  • Protein Binding
  • Protein Glutamine gamma Glutamyltransferase 2
  • Signal Transduction
  • Snail Family Transcription Factors
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transglutaminases / chemistry
  • Transglutaminases / metabolism
  • Transglutaminases / physiology*
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Homeodomain Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Snail Family Transcription Factors
  • TGM2 protein, human
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Guanosine Triphosphate
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins