期刊
ONCOGENE
卷 26, 期 18, 页码 2563-2573出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210048
关键词
apoptosis; brain tumor; tissue transglutaminase 2 inhibitors; stroma; U87MG; BCNU
资金
- NCI NIH HHS [P30 CA91842, T32CA009547, P50 CA94056] Funding Source: Medline
- NIDDK NIH HHS [R01 DK63158] Funding Source: Medline
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. 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- neoplastic 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, N-1-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.
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