Extracellular Tissue Transglutaminase Activates Noncanonical NF-κB Signaling and Promotes Metastasis in Ovarian Cancer

Abstract

Tissue transglutaminase (TG2) is a multifunctional protein that binds to fibronectin and exerts protein transamidating activity in the presence of Ca(2+). We previously reported that TG2 is upregulated in ovarian tumors and enhances intraperitoneal (i.p.) metastasis. TG2 is secreted abundantly in ovarian cancer (OC) ascites as an active enzyme, yet its function in the extracellular compartment remains unknown. To study the distinct functions of secreted TG2, we used recombinant His6-tagged TG2 and catalytically inactive enzyme in vitro and in vivo. By using i.p. and orthotopic ovarian xenografts, we show that extracellular transglutaminase promoted OC peritoneal metastasis. The main pathway activated by extracellular TG2 was noncanonical nuclear factor-kappa B (NF-κB) signaling, and the enzymatic function of the protein was required to induce phosphorylation of IκB kinase α and processing of the precursor protein p100 into the active p52 subunit. A specific target of TG2-activated p52/RelB complex is the hyaluronan receptor, CD44. Noncanonical NF-κB activation by extracellular TG2 induced CD44 up-regulation and epithelial-to-mesenchymal transition, contributing to increased cancer cell invasiveness and OC peritoneal dissemination. Taken together, our data support that noncanonical NF-κB activation is the pathway through which extracellular TG2 promotes OC metastasis.

The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer

“…The increased levels of extracellular Gαh have been shown to promote breast cancer metastasis by recruiting integrin-related signaling cascades [10, 23]. Similar findings were found in ovarian cancer where extracellular Gαh promotes metastasis via activating the NF-κB signaling axis [24]. Conversely, here, we show that the increased levels of extracellular Gαh refers to a favorable prognosis in breast cancer patients.…”

Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival

“…Ultimately, NC9 causes ECS cell apoptosis and reduced viability. This is particularly interesting, as stem cells are known to suppress apoptotic signaling pathways to enhance survival, and it is possible that TG2 has an important role in mediating this activity (26, 27, 41). Fluorescein cadaverine, a competitive substrate inhibitor of TG2 (42), also suppresses spheroid growth.…”

Transglutaminase 2 modulation of NF-κB signaling in astrocytes is independent of its ability to mediate astrocytic viability in ischemic injury

“…The particular activating stimulus and the specific subunits that are activated all determine the role that NF-κB plays in mediating cell death or survival (Mattson and Camandola, 2001; Mincheva-Tasheva and Soler, 2013; Pizzi et al, 2009; Ridder and Schwaninger, 2009; Zhang et al, 2005). TG2 has been shown to enhance NF-κB signaling in tumor cell lines, which leads to an increase in their survival (Cao et al, 2008; Han et al, 2014; Jang et al, 2010; Mann et al, 2006; Yakubov et al, 2013). It is thought that its role in activating signaling is either by facilitating its translocation to the nucleus or inducing upstream signaling via an extracellular mechanism (Han et al, 2014; Mann et al, 2006; Yakubov et al, 2013).…”

“…TG2 has been shown to enhance NF-κB signaling in tumor cell lines, which leads to an increase in their survival (Cao et al, 2008; Han et al, 2014; Jang et al, 2010; Mann et al, 2006; Yakubov et al, 2013). It is thought that its role in activating signaling is either by facilitating its translocation to the nucleus or inducing upstream signaling via an extracellular mechanism (Han et al, 2014; Mann et al, 2006; Yakubov et al, 2013). …”