We have previously shown that tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell survival via binding to the Fn14 receptor, activation of the NF-kappaB pathway, and upregulation of BCL-X(L) gene expression.
To elucidate the functional consequences of promoter methylation in the identified target death receptor 4 (DR4), we investigated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated and anti-DR4-mediated apoptosis in glioma cell lines (U373 and A172) with loss of DR4 and one glioma cell line (LN18) with robust DR4 expression.
Previous studies have shown that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has significant apoptosis-inducing activity in some glioma cell lines, although many lines are either moderately or completely resistant, which has limited the therapeutic applicability of this agent.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the Rho guanosine triphosphatase family member Rac1.
To define novel pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs).
We show that in 3D CL matrix, interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), cytokines which are elevated in gliomas in vivo, increased glioma cell invasiveness with correspondent elevation of MMP-2 and MMP-9.
In addition, resveratrol repressed nuclear factor kappa B (NF-κB) activation and down-regulated mRNA expression of urokinase plasminogen activator (uPA) and its receptor in TNF-α-treated glioma cells.
Sensitization of TNFalpha activated glioma cells to apoptosis by Ebselen involved 2 pathways: (i) abrogation of TNFalpha induced NF-kappaB activation and (ii) induction of Fas-associated death inducing signaling complex (DISC) formation.
Here we investigated the sensitivity of a panel of glioma cell lines (U87, U251, U343, U373, MZ-54, and MZ-18) to apoptosis induced by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL in combination with gamma irradiation, and TRAIL in combination with proteasome inhibitors (MG132 and epoxomicin).
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) superfamily, can stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB.
While this work calls into question previous studies that have used the B-D13 antibody to assess IL13Rα2 expression, it also suggests that TNF may have significant effects on glioma biology by up-regulating VCAM-1.
Our therapeutic strategy was to use human bone marrow-derived mesenchymal stromal cells (hMSCs) as a cellular vehicle for the targeted delivery and local production of the biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) at the glioma tumor site. hMSCs were transduced with a lentivirus expressing secretable TRAIL (S-TRAIL) and mCherry (red fluorescent protein).
This ability of CK2-Is to sensitize glioma to TNFα-induced death via multiple mechanisms involving abrogation of NF-κB activation, reactivation of wild-type p53 function and SIRT1 inhibition warrants investigation.
These findings demonstrate the effectiveness of local IFNgamma and TNFalpha gene transfer as a treatment strategy for glioma and illustrate possible physiological pathways responsible for the therapeutic benefit observed.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows a strong apoptosis-inducing effect on a variety of cancer cells including glioma.
The role of the DR5-mediated extrinsic apoptotic pathway was further studied in the three human glioma cell lines; 50 ng/ml of the DR5 ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and 2 microM 2-ME showed no synergism, as determined by MTT assays.
The therapeutic use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in malignant cells, including gliomas, and is currently in anticancer clinical trials.
Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A).
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has potent antitumor effects in glioma cell lines but has shown little clinical benefit for patients.