Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells.
BACKGROUND
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.
Department of Experimental Therapeutics, The University of Texas M.D., Anderson Cancer Center, 1901 East Road, 4SCR3,1006, Houston, TX 77030, USA.
Anupam
A
Kumar
Jia
J
Xu
Bokyung
B
Sung
Santosh
S
Kumar
Dihua
D
Yu
Bharat B
BB
Aggarwal
Kapil
K
Mehta
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D020134:Catalytic Domain; D002465:Cell Movement; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000201:enzymology / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006160:Guanosine Triphosphate / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D011503:Transglutaminases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C000717608:TGM2 protein, human; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D006160:Guanosine Triphosphate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins