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TRAIL/Apo2L ligands induce apoptosis in malignant rhabdoid tumor cell lines
Shinobu Yoshida1, Tsutomu Narita, Shigeki Koshida
1Department of Pediatrics, Shiga University of Medical Science, Tsukinowa-cho, Seta, Shiga 520-2192, Japan.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a potent inducer of apoptosis in various cancer cells, whereas normal cells are not sensitive to TRAIL-mediated apoptosis. Four TRAIL/Apo2L receptors (DR4, DR5, DcR1, and DcR2) have been identified. DR4 and DR5 have a death domain, whereas DcR1 and DcR2 are called decoy receptors because of their incomplete or lack of a death domain. Malignant rhabdoid tumor (MRT) is an aggressive neoplasm showing a poor prognosis because of its resistance to chemotherapeutic agents. In this study, we examined whether TRAIL could induce apoptotic cell death in MRT cell lines. We found that although half of the MRT cell lines examined were sensitive to TRAIL/Apo2L, Western blot analysis revealed that the expression of DcR2 was low in TRAIL-sensitive MRT cells. We examined the effect of doxorubicin on the expression levels of TRAIL receptors and its enhancement on the susceptibility of MRT cell lines to TRAIL. Western blot and flow cytometric analyses revealed that doxorubicin significantly increased the expression of DR5, and somewhat up-regulated the expression of DR4 and DcR2. Moreover, doxorubicin, NF-kappaB inhibitor (SN50), and PI3-kinase/Akt inhibitor (wortmannin, LY294002) enhanced the susceptibility of MRT cell lines to TRAIL/Apo2L-induced apoptosis. These results suggest that TRAIL/Apo2L may provide the basis for clinical trials of TRAIL-based treatment to improve the outcome of MRT patients.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) shows potential for treating malignant rhabdoid tumors (MRT). TRAIL-sensitive MRT cells have low DcR2 expression, and drug treatments can enhance TRAIL-induced apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induces apoptosis in cancer cells but not normal cells.
- Malignant rhabdoid tumor (MRT) is an aggressive cancer with poor prognosis due to chemotherapy resistance.
- TRAIL/Apo2L exerts its function through receptors DR4, DR5, DcR1, and DcR2.
Purpose of the Study:
- To investigate the efficacy of TRAIL/Apo2L in inducing apoptosis in MRT cell lines.
- To explore the role of TRAIL receptor expression in TRAIL sensitivity of MRT cells.
- To evaluate the potential of combining TRAIL/Apo2L with other agents to enhance MRT cell apoptosis.
Main Methods:
- Western blot analysis to assess protein expression levels of TRAIL receptors.
- Flow cytometry to analyze apoptosis induction.
- Treatment of MRT cell lines with TRAIL/Apo2L, doxorubicin, NF-kappaB inhibitor (SN50), and PI3-kinase/Akt inhibitors (wortmannin, LY294002).
Main Results:
- Half of the examined MRT cell lines were sensitive to TRAIL/Apo2L.
- TRAIL-sensitive MRT cells exhibited low expression of the decoy receptor DcR2.
- Doxorubicin treatment significantly increased DR5 expression and moderately upregulated DR4 and DcR2.
- Doxorubicin, SN50, and PI3-kinase/Akt inhibitors enhanced MRT cell susceptibility to TRAIL/Apo2L-induced apoptosis.
Conclusions:
- TRAIL/Apo2L demonstrates potential as a therapeutic agent for malignant rhabdoid tumors.
- Modulating TRAIL receptor expression, particularly decreasing decoy receptors like DcR2, may enhance TRAIL efficacy.
- Combination therapies involving TRAIL/Apo2L with chemotherapy or signaling pathway inhibitors show promise for improving MRT treatment outcomes.