Epithelial-to-Mesenchymal Transition and Ovarian Tumor Progression Induced by Tissue Transglutaminase

Abstract

Tissue transglutaminase (TG2), an enzyme that catalyzes Ca 2+ -dependent aggregation and polymerization of proteins, is overexpressed in ovarian cancer cells and tumors. We previously reported that TG2 facilitates tumor dissemination using an i.p. xenograft model. Here we show that TG2 modulates epithelial-to-mesenchymal transition (EMT), contributing to increased ovarian cancer cell invasiveness and tumor metastasis. By using stable knockdown and overexpression in epithelial ovarian cancer cells, we show that TG2 induces a mesenchymal phenotype, characterized by cadherin switch and invasive behavior in a Matrigel matrix. This is mediated at the transcriptional level by altering the expression levels and function of several transcriptional repressors, including Zeb1. One mechanism through which TG2 induces Zeb1 is by activating the nuclear factor-κB complex. The effects of TG2 on ovarian cancer cell phenotype and invasiveness translate into increased tumor formation and metastasis in vivo, as assessed by an orthotopic ovarian xenograft model. Highly expressed in ovarian tumors, TG2 promotes EMT and enhances ovarian tumor metastasis by activating oncogenic signaling. [Cancer Res 2009;69(24):9192-201]

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

“…The implications of our study are several. First, we demonstrate that activation of TGF-b signaling in OC cells induces the expression and function of TG2, an enzyme we previously linked to OC metastasis (Satpathy et al, 2007;Shao et al, 2009). The specificity of TGF-b's effect is demonstrated as TG2 induction is blocked by a neutralizing antibody or a TGF-b receptor kinase inhibitor.…”

“…We reported that TG2 is upregulated in ovarian tumors Satpathy et al, 2007) and has a critical role in the process of epithelial-to-mesenchymal transition (EMT), a hallmark of cancer progression. This translates into increased ovarian cancer (OC) cell invasiveness ) and intraperitoneal tumor dissemination (Satpathy et al, 2007;Shao et al, 2009). The involvement of TG2 in EMT and tumor dissemination led to the hypothesis that its expression and function are induced by transforming growth factor (TGF)-b, a key regulator of metastasis.…”

Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

“…TGase 2 (EC2.1.2.13) is a crosslinking enzyme that has been implicated in numerous cellular pathways, including cancer cell proliferation, migration, angiogenesis, epithelial mesenchymal transition and drug resistance (Verma and Mehta, 2007;Iismaa et al, 2009;Shao et al, 2009;Seo et al, 2010). A series of studies have shown that the induction of TGase 2 contributes to constitutive nuclear factor-kB (NF-kB) activation via polymerization of the inhibitor of NF-kB (Lee et al, 2004;Kim et al, 2006;Park et al, 2006), and that this is one of the mechanisms of drug resistance in cancer cells (Mehta et al, 2004;Herman et al, 2006;Kim et al, 2006Kim et al, , 2008Kim et al, , 2009Park et al, 2006;Gangadharan et al, 2009).…”

Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle

“…Cell viability was confirmed by trypan blue exclusion. For the generation of orthotopic ovarian tumor models, 10 μL of 1 ×10 6 A2780 cells or SKOV3-ip cells containing luciferase (A2780-luc) were injected into the ovaries of nude mice (ages 6-8 wk) (30,31).…”