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Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells
Taka-aki Matsui1, Yoshihiro Sowa, Tatsushi Yoshida
1Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Abstract:
Sulforaphane (SFN), a naturally occurring isothiocyanate, is an attractive agent because of its potent anticancer effects. SFN suppresses the proliferation of various cancer cells in vitro and in vivo. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is also one of the most promising candidates for cancer therapeutics owing to its ability to selectively induce apoptosis in tumor cells. In this study, we report that SFN enhances TRAIL-induced apoptosis in human osteosarcoma cells, Saos2 and MG63. The apoptosis induced by co-treatment with SFN and TRAIL was markedly blocked by a dominant negative form of the TRAIL receptor or caspase inhibitors. The combined use of SFN and TRAIL effectively induced Bid cleavage and the activation of caspases 8, 10, 9 and 3 at ineffective concentrations for each agent. SFN upregulated the expression of death receptor 5 (DR5), a receptor for TRAIL, at mRNA and protein levels in a dose-dependent manner. In addition, the SFN-mediated sensitization to TRAIL was reduced by DR5 siRNA, suggesting that the sensitization was at least partially mediated through the induction of DR5 expression. Furthermore, SFN sensitized TRAIL-induced apoptosis in a p53-independent manner. On the other hand, SFN neither induced DR5 protein expression or enhanced TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. Thus, combined treatment with SFN and TRAIL might be a promising therapy for osteosarcoma.
Insights
Sulforaphane (SFN) boosts TRAIL-induced apoptosis in osteosarcoma cells by increasing death receptor 5 (DR5) expression. This combined therapy shows promise for osteosarcoma treatment, acting independently of p53 and sparing normal cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Sulforaphane (SFN) is a natural isothiocyanate with demonstrated anticancer properties.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent due to its selective tumor cell apoptosis induction.
Purpose of the Study:
- To investigate the synergistic effect of SFN and TRAIL on human osteosarcoma cells.
- To elucidate the molecular mechanisms underlying SFN's enhancement of TRAIL-induced apoptosis.
Main Methods:
- Co-treatment of Saos2 and MG63 osteosarcoma cells with SFN and TRAIL.
- Assessment of apoptosis using dominant-negative TRAIL receptor and caspase inhibitors.
- Analysis of Bid cleavage and caspase activation (caspases 8, 10, 9, 3).
- Evaluation of death receptor 5 (DR5) expression via mRNA, protein levels, and siRNA.
- Investigation of p53-dependency and effects on normal peripheral blood mononuclear cells.
Main Results:
- SFN significantly enhanced TRAIL-induced apoptosis in osteosarcoma cells.
- Apoptosis was blocked by TRAIL receptor antagonists and caspase inhibitors, confirming the pathway.
- Combined SFN and TRAIL induced key apoptosis markers (Bid cleavage, caspase activation) at lower concentrations.
- SFN dose-dependently upregulated DR5 expression, and DR5 knockdown reduced SFN's sensitization effect.
- The sensitization effect was independent of p53 and did not occur in normal cells.
Conclusions:
- SFN sensitizes osteosarcoma cells to TRAIL-induced apoptosis, at least partially via DR5 upregulation.
- The combination therapy is effective and selective, sparing normal cells.
- Combined SFN and TRAIL represents a potential therapeutic strategy for osteosarcoma.
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