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Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

Oncogene volume 26, pages 2563–2573 (2007)Cite this article

Abstract

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 cell–extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin 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,N′-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 fibronectin 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.

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Acknowledgements

This work is supported by grants from the Barnes-Jewish Hospital and Alvine Pharmaceuticals (KMR); the NIH R01 DK63158 (CK) and P50 CA94056 (DP-W); the NCI T32CA009547 post-doctoral fellowship (CRM); and the Stanford-NIH Biotechnology Training Grant (MS). We thank the Alvin J Siteman Cancer Center at Washington University School of Medicine for the use of the Tissue Procurement Core which provided human glioblastoma frozen specimens (NCI Cancer Center Support Grant #P30 CA91842).

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Authors and Affiliations

  1. Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, USA

    L Yuan & K M Rich

  2. Departments of Chemistry and Chemical Engineering,

    M Siegel, K Choi & C Khosla

  3. Stanford University, Stanford, CA, USA

    M Siegel, K Choi & C Khosla

  4. Division of Neuropathology, Washington University School of Medicine, St Louis, MO, USA

    C R Miller

  5. Departments of Molecular Biology and Pharmacology and Radiology, Washington University School of Medicine, St Louis, MO, USA

    E N Jackson & D Piwnica-Worms

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  1. L Yuan
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  2. M Siegel
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Correspondence to K M Rich.

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Yuan, L., Siegel, M., Choi, K. et al. Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. Oncogene 26, 2563–2573 (2007). https://doi.org/10.1038/sj.onc.1210048

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