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Oncogene (2007) 26, 25632573 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc
ORIGINAL ARTICLE
Transglutaminase 2 inhibitor, KCC009, disrupts bronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy
L Yuan1, M Siegel2, K Choi2, C Khosla2, CR Miller3, EN Jackson4, D Piwnica-Worms4 and KM Rich1
1Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, USA; 2Departments of Chemistry and Chemical Engineering; Stanford University, Stanford, CA, USA; 3Division of Neuropathology, Washington University School of Medicine, St Louis, MO, USA and 4Departments of Molecular Biology and Pharmacology and Radiology, Washington University School of Medicine, St Louis, MO, USA
Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cellextracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunouorescent studies showed increased staining of bronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neo-plastic brain parenchyma secrete high levels of TG2 and bronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of bronectin in the ECM. Treatment with KCC009 blocked the remodeling of bronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N0-bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of bronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.
Oncogene (2007) 26, 25632573. doi:10.1038/sj.onc.1210048; published online 13 November 2006
Keywords: apoptosis; brain tumor; tissue transglutaminase 2 inhibitors; stroma; U87MG; BCNU
Introduction
Glioblastomas are among the most difcult malignant neoplasms to treat with median survival after diagnosis of about 12 months (Castro et al., 2003). One reason for failure to achieve long-term survival in patients with glioblastoma is attributed to high resistance to apoptosis after treatment with radiation or chemotherapy. Glioblastomas have developed...