Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 20, Issue 1, Pages 205-212Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.20.1.205-212.2000
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Funding
- NIDDK NIH HHS [DK48845, DK37871, R01 DK037871] Funding Source: Medline
- NIGMS NIH HHS [GM303024] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK037871, R01DK048845] Funding Source: NIH RePORTER
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Chemotherapeutic genotoxins induce apoptosis in epithelial-cell-derived cancer cells. The death receptor ligand TRAIL also induces apoptosis in epithelial-cell-derived cancer cells but generally fails to induce apoptosis in nontransformed cells. We show here that the-treatment of four different epithelial cell lines with the topoisomerase II inhibitor etoposide in combination with TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) induces a synergistic apoptotic response. The mechanism of the synergistic effect results from the etoposide-mediated increase in the expression of the death receptors 4 (DR4) and 5 (DR5). Inhibition of NF-kappa B activation by expression of kinase-inactive MEK kinase 1(MEKK1) or dominant-negative I kappa B (Delta I kappa B) blocked the increase in DR4 and DR5 expression following etoposide treatment. Addition of a soluble decoy DR4 fusion protein (DR4:Fc) to cell cultures reduced the amount of etoposide-induced apoptosis in a dose-dependent manner. The addition of a soluble TNF decoy receptor (TNFR:Fc) was without effect, demonstrating the specificity of DR4 binding ligands in the etoposide-induced apoptosis response. Thus, genotoxin treatment in combination with TRAIL is an effective inducer of epithelial-cell derived tumor cell apoptosis relative to either treatment alone.
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