Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis |
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Authors: | Penny Clarke Kenneth L Tyler |
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Institution: | (1) Departments of Neurology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B182, Denver, Colorado 80262, USA;(2) Departments of Medicine, Microbiology and Immunology, Denver Veterans Affairs Medical Center, Denver, Colorado 80220, USA |
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Abstract: | Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) shows promise as a chemotherapeutic agent. However, many human
cancer cells are resistant to killing by TRAIL. We have previously demonstrated that reovirus infection increases the susceptibility
of human lung (H157) and breast (ZR75-1) cancer cell lines to TRAIL-induced apoptosis. We now show that reovirus also increases
the susceptibility of human ovarian cancer cell lines (OVCAR3, PA-1 and SKOV-3) to TRAIL-induced apoptosis. Reovirus-induced
increases in susceptibility of OVCAR3 cells to TRAIL require virus uncoating and involve increased activation of caspases
3 and 8. Reovirus infection results in the down-regulation of cFLIP (cellular FLICE inhibitory protein) in OVCAR3 cells. Down-regulation
of cFLIP following treatment of OVCAR3 cells with antisense cFLIP oligonucleotides or PI3 kinase inhibition also increases
the susceptibility of OVCAR3 cells to TRAIL-induced apoptosis. Finally, over-expression of cFLIP blocks reovirus-induced sensitization
of OVCAR3 cells to TRAIL-induced apoptosis. The combination of reovirus and TRAIL thus represents a promising new therapeutic
approach for the treatment of ovarian cancer. |
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Keywords: | Reovirus TRAIL cFLIP OVCAR3 Apoptosis |
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