Abstract
Plant-derived lignans have numerous biological effects including anti-tumor and anti-inflammatory activities. Screening of purified constituents of Rubia philippinensis from human glioblastoma cells resistant to TNF-related apoptosis-inducing ligand (TRAIL) has suggested that the lignan pinoresinol was a highly active TRAIL sensitizer. Here we show that treatment with nontoxic doses of pinoresinol in combination with TRAIL induced rapid apoptosis and caspase activation in many types of glioblastoma cells, but not in normal astrocytes. Analyses of apoptotic signaling events revealed that pinoresinol enhanced the formation of TRAIL-mediated death-inducing signaling complex (DISC) and complete processing of procaspase-8 within the DISC in glioblastoma cells, in which caspase-8 was inactivated. Mechanistically, pinoresinol downregulated the expression of cellular FLICE-inhibitory protein (cFLIPL) and survivin through proteasome-mediated degradation, without affecting death receptors or downstream intracellular apoptosis-related proteins. Furthermore, the sensitization of TRAIL-mediated apoptosis by pinoresinol strictly depended on the expression level of cFLIPL, which was regulated through de novo protein synthesis, rather than by NF-κB or p53 signaling. Taken together, our results indicate that pinoresinol facilitates DISC-mediated caspase-8 activation by targeting cFLIPL in an early event in apoptotic signaling, which provides a potential therapeutic module for TRAIL-based chemotherapy.
Highlights
The use of TNF-related apoptosis-inducing ligand (TRAIL) in cancer therapy has long been thought as an attractive strategy because it can selectively target cancer cells without affecting the majority of normal human cells[1]
Our findings revealed novel evidence that the prominent sensitizing effects of pinoresinol against TRAIL-mediated apoptosis involved the downregulation of levels of cellular FLICE-inhibitory protein by a mechanism involving de novo protein synthesis
We characterized a set of major compounds obtained from R. philippinenesis to identify active constituents that synergistically sensitized the cytotoxic effects of TRAIL in TRAIL-resistant glioblastoma cells (Supplementary Table S1, Supplementary Figs 1–33)
Summary
The use of TNF-related apoptosis-inducing ligand (TRAIL) in cancer therapy has long been thought as an attractive strategy because it can selectively target cancer cells without affecting the majority of normal human cells[1]. The genus Rubia (family Rubiaceae), a perennial herb, is widely distributed worldwide It is one of the most attractive plant resources because of its potent and wide spectrum of in vivo and in vitro biological activities, which include anti-cancer, anti-inflammatory, and anti-angiogenic effects[13,14,15]. Several studies have reported the anti-cancer effects of Rubia species, the effects of the principle constituents of R. philippinensis on DR-mediated cell death, during TRAIL sensitization, have not yet been determined. As part of our ongoing search to identify potential therapeutic approaches for sensitizing TRAIL-mediated cell death, we tested 33 compounds isolated from R. philippinensis and found that nontoxic doses of pinoresinol, a lignan, drastically sensitized cancer cells against TRAIL-induced apoptosis. Our findings revealed novel evidence that the prominent sensitizing effects of pinoresinol against TRAIL-mediated apoptosis involved the downregulation of levels of cellular FLICE-inhibitory protein (cFLIPL) by a mechanism involving de novo protein synthesis
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