Tissue transgluaminase 2 expression in meningiomas

Abstract

Meningiomas are common intracranial tumors that occur in extra-axial locations, most often over the cerebral convexities or along the skull-base. Although often histologically benign these tumors frequently present challenging clinical problems. Primary clinical management of patients with symptomatic tumors is surgical resection. Radiation treatment may arrest growth or delay recurrence of these tumors, however, meningioma cells are generally resistant to apoptosis after treatment with radiation. Tumor cells are known to alter their expression of proteins that interact in the ECM to provide signals important in tumor progression. One such protein, fibronectin, is expressed in elevated levels in the ECM in a number of tumors including meningiomas. We recently reported that levels of both extracellular fibronectin and tissue transglutaminase 2 (TG2) were increased in glioblastomas. We examined the expression of fibronectin and its association TG2 in meningiomas. Both fibronectin and TG2 were strongly expressed in all meningiomas studied. TG2 activity was markedly elevated in meningiomas, and TG2 was found to co-localize with fibronectin. Treatment of meningiomas with the small molecule TG2 inhibitor, KCC009, inhibited the binding of TG2 to fibronectin and blocked disposition of linear strands of fibronectin in the ECM. KCC009 treatment promoted apoptosis and enhanced radiation sensitivity both in cultured IOMM-Lee meningioma cells and in meningioma tumor explants. These findings support a potential protective role for TG2 in meningiomas.

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

“…Hematogenous metastasis to lung and other organs of intravenously injected tumor cells was increased, although individual metastasis size was smaller, in TG2 Ϫ/Ϫ compared with wild-type mice (75). Inhibition of TG2, by treatment with TG2 inhibitors (306,307), antisense (108), ribozyme (108) or RNAi (13,112,138,308) technologies, sensitized cancer cells to chemotherapeutic agents by disrupting fibronectin assembly in the ECM and promoting cell death or autophagy (306,308). Although it is not yet clear which location or biochemical function of TG2 is involved in these effects, it appears that TG2 and FXIII-A have opposing roles in cancer progression.…”

Tissue transglutaminase: a new target to reverse cancer drug resistance

“…Irreversible inhibitors such as KCC009 or KCA075 prevent enzyme activity by covalently modifying the enzyme, thereby preventing substrate binding. These inhibitors, as reported in the previous sections, have been used to enhance both in vitro and in vivo chemotherapy in several preclinical cancer models, such as ovarian, non-small cell lung, melanoma, breast and colon cancers as well as glioblastoma and meningioma (Yuan et al 2005, 2007, 2008, 2011; Cao et al 2008; Satpathy et al 2009; Frese-Schaper et al 2010). Reversible TG2 inhibitors block substrate access to the enzyme active site without covalently modifying the enzyme.…”

Characterization of transglutaminase type II role in dendritic cell differentiation and function

“…TG2 cross-linking activity was inhibited by addition of different concentrations (10, 50, and 100 M) of the KCC009 inhibitor (compound 1b; see refs. [25][26][27][28]) on Day 0 of culture.…”