A dual role for Caspase8 and NF-kappa B interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival
AuthorHernandez, L; Kim, MK; Noonan, AM; Sagher, E; Kohlhammer, H; Wright, G; Lyle, LT; Steeg, PS; Anver, M; Bowtell, DD; ...
Source TitleCell Death Discovery
University of Melbourne Author/sBowtell, David
AffiliationSir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsHernandez, L., Kim, M. K., Noonan, A. M., Sagher, E., Kohlhammer, H., Wright, G., Lyle, L. T., Steeg, P. S., Anver, M., Bowtell, D. D. & Annunziata, C. M. (2015). A dual role for Caspase8 and NF-kappa B interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival. CELL DEATH DISCOVERY, 1 (1), https://doi.org/10.1038/cddiscovery.2015.53.
Access StatusOpen Access
Ovarian cancer is a deadly disease characterized by primary and acquired resistance to chemotherapy. We previously associated NF-κB signaling with poor survival in ovarian cancer, and functionally demonstrated this pathway as mediating proliferation, invasion and metastasis. We aimed to identify cooperating pathways in NF-κB-dependent ovarian cancer cells, using genome-wide RNA interference as a loss-of-function screen for key regulators of cell survival with IKKβ inhibition. Functional genomic screen for interactions with NF-κB in ovarian cancer showed that cells depleted of Caspase8 died better with IKKβ inhibition. Overall, low Caspase8 was associated with shorter overall survival in three independent gene expression data sets of ovarian cancers. Conversely, Caspase8 expression was markedly highest in ovarian cancer subtypes characterized by strong T-cell infiltration and better overall prognosis, suggesting that Caspase8 expression increased chemotherapy-induced cell death. We investigated the effects of Caspase8 depletion on apoptosis and necroptosis of TNFα-stimulated ovarian cancer cell lines. Inhibition of NF-κB in ovarian cancer cells switched the effects of TNFα signaling from proliferation to death. Although Caspase8-high cancer cells died by apoptosis, Caspase8 depletion downregulated NF-κB signaling, stabilized RIPK1 and promoted necroptotic cell death. Blockage of NF-κB signaling and depletion of cIAP with SMAC-mimetic further rendered these cells susceptible to killing by necroptosis. These findings have implications for anticancer strategies to improve outcome for women with low Caspase8-expressing ovarian cancer.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References