Paxilline enhances TRAIL-mediated apoptosis of glioma cellsviamodulation of c-FLIP, survivin and DR5

Abstract

Abbreviations: FADD, fas-associated protein with death domain; TRAIL, tumor necrosis factor-related apoptosis-induced ligand AbstractTumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. Here, we report that paxilline, an indole alkaloid from Penicillium paxilli, can sensitize various glioma cells to TRAIL-mediated apoptosis. While treatment with TRAIL alone caused partial processing of caspase-3 to its p20 intermediate in TRAIL-resistant glioma cell lines, co-treatment with TRAIL and subtoxic doses of paxilline caused complete processing of caspase-3 into its active subunits. Paxilline treatment markedly upregulated DR5, a receptor of TRAIL, through a CHOP/GADD153-mediated process. In addition, paxilline treatment markedly downregulated the protein levels of the short form of the cellular FLICE-inhibitory protein (c-FLIP S ) and the caspase inhibitor, survivin, through proteasome-mediated degradation. Taken together, these results show that paxilline effectively sensitizes glioma cells to TRAIL-mediated apoptosis by modulating multiple components of the death receptor-mediated apoptotic pathway. Interestingly, paxilline/TRAIL co-treatment did not induce apoptosis in normal astrocytes, nor did it affect the protein levels of CHOP, DR5 or survivin in these cells. Thus, combined treatment regimens involving paxilline and TRAIL may offer an attractive strategy for safely treating resistant gliomas.

Growth Inhibitory Effect of (E)-2,4-bis(p-hydroxyphenyl)-2-Butenal Diacetate through Induction of Apoptotic Cell Death by Increasing DR3 Expression in Human Lung Cancer Cells

“…The extrinsic pathway of apoptosis requires induction of death receptors (Kang et al , 2011; Zhu et al , 2011). Therefore, we investigated the effect of (E)-2,4-bis( p -hydroxyphenyl)-2-butenal diacetate on the expression of death receptors.…”

“…It is well-known that apoptosis can be induced by stimulation of DRs including TNFR1/2, DR3, DR4, DR5, DR6 and Fas by their respective ligands (Kang et al , 2011; Zhu et al , 2011). Therefore, these receptors emerged as attractive targets for anti-cancer therapeutics.…”

Combination Treatment for Glioblastoma Cells with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Oncolytic Adenovirus Delta-24

“…Histone deacetylase inhibitors combined with TRAIL have been shown to induce apoptosis at least in part by c-myc-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP) (29). Paxilline can also sensitize TRAIL-resistant glioma cells to TRAILinduced apoptosis (30).…”

Kurarinone promotes TRAIL-induced apoptosis by inhibiting NF-κB-dependent cFLIP expression in HeLa cells

“…However, TRAIL does not exclusively activate the apoptotic pathway, but also induces NF-κB-dependent up-regulation of anti-apoptotic genes, including cFLIP (Rae et al, 2007; Romagnoli et al, 2007; Plantivaux et al, 2009). Our group and others demonstrated that siRNA-mediated knockdown of cFLIP increases TRAIL-induced apoptosis (Kang et al, 2004, 2011). These results suggest that inhibition of the NF-κB pathway promotes TRAIL-induced apoptosis of tumor cells.…”