Ophiopogonin B sensitizes TRAIL-induced apoptosis through activation of autophagy flux and downregulates cellular FLICE-like inhibitory protein
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Uddin MD. Nazim1,*, Jae-Kyo Jeong1,* and Sang-Youel Park1
1Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea
*These authors are equal contribution to this work
Sang-Youel Park, email: [email protected]
Keywords: ophiopogonin; autophagy; TRAIL; apoptosis; lung cancer cells
Received: September 19, 2017 Accepted: December 15, 2017 Published: December 23, 2017
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL), a type II transmembrane protein, belongs to the TNF superfamily. Compared to other family members, TRAIL is a promising anti-cancer agent that can selectively induce apoptosis of various types of transformed cells and xenografts, with negligible cytotoxicity against normal tissues. Ophiopogonin B is a bioactive ingredient of Radix Ophiopogon japonicus, which is frequently used in traditional Chinese medicine to treat cancer. In this study, we report that Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is the key determinant mediating TRAIL resistance in A549 cells and Ophiopogonin B downregulates c-FLIP and enhances TRAIL-induced apoptosis by activating autophagy flux. In addition, treatment with Ophiopogonin B resulted in a slight increase in the conversion of LC3-I to LC3-II and significantly decreased p62 expression levels in a dose-dependent manner. This indicates that Ophiopogonin B induces autophagy flux activation in human lung cancer cells. Inhibiting autophagy flux by applying a specific inhibitor ATG5 siRNA with Ophiopogonin B mediated enhancement of TRAIL effects. These data demonstrate that downregulation of c-FLIP by Ophiopogonin B enhances TRAIL-induced tumor cell death by activating autophagy flux in TRAIL-resistant A549 cells, and also suggests that Ophiopogonin B combined with TRAIL may be a successful therapeutic strategy for TRAIL-resistant lung cancer cells.
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