The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression

Abstract

Tissue transglutaminase (transglutaminase type 2; TG2) is the most ubiquitously expressed member of the transglutaminase family (EC 2.3.2.13) that catalyzes specific post-translational modifications of proteins through a calcium-dependent acyl-transfer reaction (transamidation). In addition, this enzyme displays multiple additional enzymatic activities, such as guanine nucleotide binding and hydrolysis, protein kinase, disulfide isomerase activities, and is involved in cell adhesion. Transglutaminase 2 has been reported as one of key enzymes that is involved in all stages of carcinogenesis; the molecular mechanisms of action and physiopathological effects depend on its expression or activities, cellular localization, and specific cancer model. Since it has been reported as both a potential tumor suppressor and a tumor-promoting factor, the role of this enzyme in cancer is still controversial. Indeed, TG2 overexpression has been frequently associated with cancer stem cells' survival, inflammation, metastatic spread, and drug resistance. On the other hand, the use of inducers of TG2 transamidating activity seems to inhibit tumor cell plasticity and invasion. This review covers the extensive and rapidly growing field of the role of TG2 in cancer stem cells survival and epithelial⁻mesenchymal transition, apoptosis and differentiation, and formation of aggressive metastatic phenotypes.

Keywords: cancer stem cells; inflammation; metastasis; tissue transglutaminase.

Figure 1

Reactions catalyzed by type II transglutaminase or tissue transglutaminase (TG2) (from Tatsukawa et al. [62] with modifications).

Figure 2

Tumor cells, with high metastatic potential, are characterized by high levels of intracellular polyamines and low transamidase activity of TG2. This condition favors the formation of mono-(γ-glutamyl) derivatives of polyamines, preventing polymerization of intracellular proteins, in particular, those components of the cytoskeleton. It follows that cellular plasticity is high, due to the reduction of cell–cell or cell–matrix interactions, which favors cell detachment and motility. By contrast, in cells with reduced metastaticity, the transamidase activity of TG2 is higher. Hence, the polymerization of intracellular proteins is increased by the favored formation of ε-(γ-glutamyl) lysine and bis-(γ-glutamyl) polyamine derivatives. Therefore, in these cells, the plasticity is reduced and the cell–matrix interactions, mediated by integrins and TG2, are more pronounced, due to the increase in cell adhesion with extracellular matrix (ECM) (modified from Lentini et al., 2013 [17]).