Abstract
The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member which has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. However, many cancer cells remain resistant to TRAIL. In this study, we had investigated the synergistic effects of low dose fluorouracil (5-Fu) and TRAIL on TRAIL-resistant human gastric adenocarcinoma AGS cells and explored the potential mechanisms. Cell viability was analyzed by sulforhodamine B (SRB) assay and the synergistic effects were evaluated by Jin's formula and confirmed by both morphological changes under inverted microscope and flow cytometry. The expression of TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (DR5), TRAIL-R3 (decoy receptor, DcR1), TRAIL-R4 (DcR2), procaspase-3, procaspase-8, and procaspase-9 was detected by western blotting. Our results showed that there were significant synergistic effects of low dose 5-Fu and TRAIL on TRAIL-resistant AGS cells, and this effect was supposed to be mediated by decreasing DcR2 expression and increasing DR5 expression. The extrinsic and intrinsic apoptosis pathways were both activated. The data suggest that combined treatment of low dose 5-Fu and TRAIL can be an effective therapeutic approach for gastric adenocarcinoma.
Highlights
The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member capable of inducing apoptosis through caspase-dependent mechanisms
Recent studies showed that many types of cancer cells have intrinsic or acquired resistance to TRAIL-induced apoptosis [5, 7, 8], which potentially restricts its use in treatment
TRAIL resistance is a major problem of its therapy, as a considerable number of cancer cells, especially some highly malignant tumors, are resistant to apoptosis induction by TRAIL [1, 7]
Summary
The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member capable of inducing apoptosis through caspase-dependent mechanisms. DR4 and DR5 are the death receptors that signal for apoptosis, whereas DcR1 and DcR2 do not have the intracytoplasmic death domain to transduce apoptotic death signals, and they protect cells from TRAIL-mediated cell death by interfering with signaling through DR4 and DR5. Another receptor, osteoprotegerin (OPG), is a soluble receptor that may play a more prominent role in bone and myeloid cell development [2, 3]. For the clinical use of TRAIL in cancer therapy, it is extremely important to overcome TRAIL resistance
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