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

L. Yuan, M. Siegel, Kihang Choi, C. Khosla, C. R. Miller, E. N. Jackson, D. Piwnica-Worms, K. M. Rich

Research output: Contribution to journalArticle

126 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2563-2573
Number of pages11
JournalOncogene
Volume26
Issue number18
DOIs
Publication statusPublished - 2007 Apr 19
Externally publishedYes

Fingerprint

Glioblastoma
Fibronectins
Extracellular Matrix
Drug Therapy
Brain
Transglutaminases
KCC 009
transglutaminase 2
RNA Interference
Amides
Adhesives
Neoplasms
Down-Regulation
Apoptosis
Staining and Labeling
Survival
Enzymes
Therapeutics

Keywords

  • Apoptosis
  • BCNU
  • Brain tumor
  • Stroma
  • Tissue transglutaminase 2 inhibitors
  • U87MG

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. / Yuan, L.; Siegel, M.; Choi, Kihang; Khosla, C.; Miller, C. R.; Jackson, E. N.; Piwnica-Worms, D.; Rich, K. M.

In: Oncogene, Vol. 26, No. 18, 19.04.2007, p. 2563-2573.

Research output: Contribution to journalArticle

Yuan, L. ; Siegel, M. ; Choi, Kihang ; Khosla, C. ; Miller, C. R. ; Jackson, E. N. ; Piwnica-Worms, D. ; Rich, K. M. / Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. In: Oncogene. 2007 ; Vol. 26, No. 18. pp. 2563-2573.
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