Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection

Clarke, Penny; Meintzer, Suzanne M.; Spalding, Aaron C.; Johnson, Gary L.; Tyler, Kenneth L.

doi:10.1038/sj.onc.1204842

Cited by 61 publications

(70 citation statements)

References 41 publications

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“…1(A)). These results are similar to what we had previously observed following reovirus infection of ZR75-1 cells [54].…”

Section: Reovirus Increases the Susceptibility Of Ovcar3 Cells To Trasupporting

confidence: 82%

“…6). In contrast, TRAIL treatment of the TRAIL-sensitive HeLa cell line [54] resulted in a marked decrease in the expression of cFLIP L and a less dramatic but consistent decrease in cFLIP S . These results suggest that decreased levels of cFLIP expression are associated with apoptosis in TRAIL-treated cells.…”

Section: Reovirus Down-regulates Cflip In Infected Ovcar3 Cellsmentioning

confidence: 85%

“…We have previously shown that reovirus increases the susceptibility of human breast (ZR75-1) and lung (H157) cancer cells to TRAIL-induced apoptosis [54]. We next wanted to discover whether reovirus could also increase the susceptibility of human ovarian cancer cells to TRAILinduced apoptosis and to determine the mechanism by which this occurs.…”

Section: Reovirus Increases the Susceptibility Of Ovcar3 Cells To Tramentioning

confidence: 99%

“…Cells which contained condensed nuclei that stained green (acridine orange) were considered to be early apoptotic whereas cells which contained condensed nuclei that stained red (ethidium bromide) were considered to be late apoptotic. The specificity of this assay has been previously established in reovirus-infected cells using DNA laddering techniques and electron microscopy [53,54]. Cell populations were also analyzed by flow cytometry to determine intracellular levels of active caspase 8, using a fluorochrome inhibitor of caspases (FLICA, Immunochemistry Technologies, Bloomington, MN) and to determine phosphatidyl serine exposure on the outer cell membrane by annexin assay (Trevigen).…”

Section: Apoptosis Assaysmentioning

confidence: 99%

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Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Clarke

Tyler

2006

Apoptosis

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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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“…1(A)). These results are similar to what we had previously observed following reovirus infection of ZR75-1 cells [54].…”

Section: Reovirus Increases the Susceptibility Of Ovcar3 Cells To Trasupporting

confidence: 82%

Section: Reovirus Down-regulates Cflip In Infected Ovcar3 Cellsmentioning

confidence: 85%

Section: Reovirus Increases the Susceptibility Of Ovcar3 Cells To Tramentioning

confidence: 99%

Section: Apoptosis Assaysmentioning

confidence: 99%

See 2 more Smart Citations

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Clarke

Tyler

2006

Apoptosis

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“…17 Caspase 8 and JNK MAPK proteins also participate in apoptotic signaling following reoviral infection. 18 Herein, we explored whether reovirus can be used as a potential cancer therapeutic agent against cancer cells expressing CUG2, which is commonly detected in various tumor tissues. In these studies, we found that CUG2 expression confers reovirus propagation in nonpermissive NIH3T3 cells by the activation of p38 MAPK and Ras.…”

Section: Introductionmentioning

confidence: 99%

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Park

I-R

et al. 2010

Cancer Gene Ther

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As we have recently found a novel oncogene, the cancer-upregulated gene 2 (CUG2), which was elevated in a variety of tumor tissues such as the ovary, liver, lung and pancreas, we examined whether reovirus could efficiently induce cytolysis in cancer cells expressing CUG2 and thus be used as a potential cancer therapeutic agent. In this study, we describe experiments in which we use reovirus to treat NIH3T3 cells stably expressing either CUG2 (NIH-CUG2) or vector only (NIH-Vec). NIH-CUG2 cells readily support reoviral proliferation and undergo apoptosis, whereas NIH-Vec cells are highly resistant to reoviral infection and virusinduced apoptosis. This notable result may be explained by the observation that CUG2 expression inhibits PKR activation, leading to reoviral proliferation in nonpermissive NIH3T3 cells. Furthermore, reovirus infection results in almost complete regression of tumorgenic NIH-CUG2 cells in transplanted nude mice. As we found that CUG2 enhances activation of MAPK (ERK, JNK and p38), Src kinase and Ras, we examined whether CUG2 confers reoviral replication independent of the Ras or p38 MAPK signaling pathway. From these experiments we found that either inhibition of p38 MAPK or Ras blocks reoviral proliferation even in the presence of CUG2 but inhibition of ERK, JNK and Src kinase does not, indicating that activation of p38 MAPK and Ras has critical roles in reoviral replication in CUG2-expressing tumor cells. Accordingly, we propose that reovirus can be useful in the treatment of transformed cells expressing CUG2, which is commonly detected in various tumor tissues.

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Mechanisms of Apoptosis During Reovirus Infection

Clarke

Richardson-Burns

DeBiasi

et al.

Role of Apoptosis in Infection

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Reovirus infection has proven to be an excellent experimental system for studying mechanisms of virus-induced pathogenesis. Reoviruses induce apoptosis in a wide variety of cultured cells in vitro and in target tissues in vivo, including the heart and central nervous system. In vivo, viral infection, tissue injury, and apoptosis colocalize, suggesting that apoptosis is a critical mechanism by which disease is triggered in the host. This review examines the mechanisms of reovirus-induced apoptosis and investigates the possibility that inhibition of apoptosis may provide a novel strategy for limiting virus-induced tissue damage following infection.

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Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection

Cited by 61 publications

References 41 publications

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Mechanisms of Apoptosis During Reovirus Infection

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