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Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy
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Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy
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Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy
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Journal Article
Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy
2007
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
Subject
/ Animals
/ Biological and medical sciences
/ Brain Neoplasms - drug therapy
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ Control
/ Enzyme Inhibitors - pharmacology
/ Extracellular Matrix - drug effects
/ Extracellular Matrix - metabolism
/ Female
/ Fluorescent Antibody Technique
/ Fundamental and applied biological sciences. Psychology
/ GTP-Binding Proteins - antagonists & inhibitors
/ GTP-Binding Proteins - metabolism
/ Humans
/ Medicine
/ Mice
/ Molecular and cellular biology
/ Oncology
/ RNA, Small Interfering - pharmacology
/ Stroma
/ Transglutaminases - antagonists & inhibitors
/ Transglutaminases - metabolism
/ Tumors
