Transglutaminase is a tumor cell and cancer stem cell survival factor

Abstract

Recent studies indicate that cancer cells express elevated levels of type II transglutaminase (TG2), and that expression is further highly enriched in cancer stem cells derived from these cancers. Moreover, elevated TG2 expression is associated with enhanced cancer stem cell marker expression, survival signaling, proliferation, migration, invasion, integrin-mediated adhesion, epithelial-mesenchymal transition, and drug resistance. TG2 expression is also associated with formation of aggressive and metastatic tumors that are resistant to conventional therapeutic intervention. This review summarizes the role of TG2 as a cancer cell survival factor in a range of tumor types, and as a target for preventive and therapeutic intervention. The literature supports the idea that TG2, in the closed/GTP-binding/signaling conformation, drives cancer cell and cancer stem cell survival, and that TG2, in the open/crosslinking conformation, is associated with cell death.

Keywords: EMT; breast cancer; cancer stem cells; drug resistance; epidermal cancer stem cells; epithelial-mesenchymal transition; glioma; ovarian cancer; pancreatic cancer; prostate cancer; squamous cell carcinoma; transglutaminase.

Figure 1

TG2 structure and function. A: Schematic of TG2 showing the β-sandwich, catalytic core, β-barrel1, and β-barrel2 domains, and the biological functions associated with each domain. Nucleotide binding (GTP/GDP) is mainly to residues from the first and last strands (amino acids 476–482 and 580–583) of β-barrel 1, and two core domain residues (Lys-173 and Phe-174) [–150]. B: Guanine nucleotide (GTP/GDP)-bound TG2 is folded/closed. This form of TG2 is involved in intracellular signal transduction, survival, proliferation, migration, invasion, tumor formation, drug resistance, and EMT. It is also enriched in cancer stem cells and functions as a cancer stem cell survival factor. Open TG2 does not bind GTP/GDP. Instead, the transamidation (crosslinking) site is accessible to substrate and open TG2 catalyzes crosslinking of intracellular proteins and is associated with cancer cell apoptosis. Oxidation of the open form of TG2 converts it to an inactive form. The GTP/GDP binding site is indicated by a red arrow. Only closed TG2 binds GTP/GDP [19,22,151].