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Breast Cancer Research
Published in: Breast Cancer Research 1/2013

Open Access 01-02-2012 | Research article

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

Authors: Anupam Kumar, Jia Xu, Bokyung Sung, Santosh Kumar, Dihua Yu, Bharat B Aggarwal, Kapil Mehta

Published in: Breast Cancer Research | Issue 1/2013

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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.
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Metadata
Title
Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells
Authors
Anupam Kumar
Jia Xu
Bokyung Sung
Santosh Kumar
Dihua Yu
Bharat B Aggarwal
Kapil Mehta
Publication date
01-02-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2013
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3085

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