Tissue transgluaminase 2 expression in meningiomas.
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.
Yuan
Liya
L
Department of Neurological Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8057, St. Louis, MO 63110, USA.
Behdad
Amir
A
Siegel
Matthew
M
Khosla
Chaitan
C
Higashikubo
Ryuji
R
Rich
Keith M
KM
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D019204:GTP-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007555:Isoxazoles / Q000494:pharmacology; D008577:Meningeal Neoplasms / Q000378:metabolism*; D008579:Meningioma / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011700:Putrescine / Q000378:metabolism; D011827:Radiation; D046509:Tissue Culture Techniques; D011503:Transglutaminases / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005353:Fibronectins; D007555:Isoxazoles; C510621:KCC 009; C000717608:TGM2 protein, human; D014316:Tritium; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D011700:Putrescine