Sensitization of human glioblastomas to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) by NF‐κB inhibitors

Abstract

Glioblastoma is the most malignant form of primary brain tumor in adults, with no effective therapy and a low survival rate. TRAIL is a member of the TNF family, which selectively induces apoptosis in certain neoplastic cells, but not normal cells. In this study, we investigated the sensitivity of 7 human glioblastoma cell lines to TRAIL and the expression in them of TRAIL receptors. TRAIL exhibited significant cytotoxicity in 5 of 7 glioma cell lines. These glioblastoma cell lines expressed TRAIL-R2, but not TRAIL-R1, R3, or R4. However, no correlation was observed between the TRAIL sensitivity and the TRAIL-R2 expression level, suggesting that there is an additional determinant of TRAIL sensitivity.

NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition

“…Proteasome inhibitors have previously been reported to enhance TRAIL-induced apoptosis in a variety of cancers, for example glioblastoma (Kasuga et al, 2004;Kim et al, 2004;Yin et al, 2005) and prostate, colon or bladder cancer (Johnson et al, 2003), as well as primary kerationocytes (Leverkus et al, 2003). Although some potential mediators of this sensitization effect have been indicated, for example p21 (Lashinger et al, 2005), c-FLIP (Sayers et al, 2003), Bik and Bim (Nikrad et al, 2005), whereas others have been excluded, for instance Bcl-2 (Nencioni et al, 2005), Bax (He et al, 2004) and Bcl-xL (Johnson et al, 2003), the specific contribution of NF-kB to this phenomenon remained unclear.…”

Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level

“…Moreover, analysis of DR4 and DR5 expression reveals that cell lines with the lowest sensitivity to TRAIL (Rec-1, Granta-519, and JVM-2) express the highest amounts of receptors. A lack of correlation between sensitivity to TRAIL cytotoxic effect and membrane expression of its receptors has been described in other models (21,22). Although a frequent polymorphism affects the TRAIL receptor locus in MCL cells, no mutations are observed in their death domain (23).…”

The Pivotal Roles of GSK3β in Glioma Biology

“…One of the major targets of GSK3 is NF-κB, which is an intracellular protein complex that controls DNA transcription and is a pro-survival factor in glioma (Kasuga et al, 2004;Robe et al, 2004). Inhibition of GSK3 activity by GSK3 -specific inhibitors such as LiCl and by GSK3 siRNA caused a dramatic decrease in intracellular NF-κB activity in U251, T98, and U87 GBM cell lines (Kotliarova et al, 2008).…”