Abstract
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.
Highlights
Lung carcinoma is one of the principal reasons of cancer-related death worldwide [1]
We report that Cellular FLICE (FADD-like IL-1β-converting enzyme)inhibitory protein (c-FLIP) is the key determinant mediating Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) resistance in A549 cells and Ophiopogonin B downregulates c-FLIP and enhances TRAIL-induced apoptosis by activating autophagy flux
Inhibiting autophagy flux by applying a specific inhibitor ATG5 small interfering RNA (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 suggests that Ophiopogonin B combined with TRAIL may be a successful therapeutic strategy for TRAIL-resistant lung cancer cells
Summary
Lung carcinoma is one of the principal reasons of cancer-related death worldwide [1]. Only 17.4% of all lung carcinoma patients live longer than 5 years [2]. In 2012, over 1.8 million people throughout the world had lung cancer, which is estimated to have caused 1.6 million deaths worldwide [3]. Chemotherapy and radiotherapy are the main tools for cancer therapy after surgery. Commencing cancers are infrequently resistant to single method. For this group of patients, combination chemotherapy can extend the 5-year survival rate and prevent recurrence
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