A dual role for Caspase8 and NF-κB interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival.
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 IKKβinhibition. Functional genomic screen for interactions with NF-κB in ovarian cancer showed that cells depleted of Caspase8 died better with IKKβinhibition. 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 TNFαsignaling 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.
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
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L
Hernandez
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
M K
MK
Kim
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
A M
AM
Noonan
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
E
E
Sagher
Metabolism Branch, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892-1906, USA.
H
H
Kohlhammer
Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, MD 20892-1906, USA.
G
G
Wright
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
L T
LT
Lyle
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
P S
PS
Steeg
Pathology/Histotechnology Laboratory, LASP, Leidos Biomedical Research, Inc. , Frederick, MD 21702-1201, USA.
M
M
Anver
Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
D D
DD
Bowtell
Women's Malignancies Branch, National Cancer Institute , Bethesda, MD 20892-1906, USA.
C M
CM
Annunziata