The expression of proinflammatory protein tissue transglutaminase (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 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.

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

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-kappaB, is deemed essential for promoting the EMT/CSC phenotype in mammary epithelial cells.

Our results suggest that transamidation activity of TG2 is not essential for promoting its oncogenic functions and provide 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 and for reversing drug resistance and inhibiting metastasis of cancer cells.

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