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Gene array data for Fas knock-out human cancer cell line and mouse liver tissue

ABSTRACT: CD95 (also called FAS and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through induction of apoptosis. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers and many cancer cells express large quantities of CD95 and are highly sensitive to CD95 mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L. These data raise the intriguing possibility that CD95 could actually promote the growth of tumours through its nonapoptotic activities. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and c-Jun. These results demonstrate that CD95 plays a major growth promoting role during tumorigenesis and suggest that efforts to inhibit its activity rather than to enhance its activation should be considered during cancer therapy.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE21154 | GEO | 2010/04/02

SECONDARY ACCESSION(S): PRJNA126599

REPOSITORIES: GEO

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Gene array data for Fas knock-out human cancer cell line and mouse liver tissue

Project description:CD95 (also called FAS and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through induction of apoptosis. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers and many cancer cells express large quantities of CD95 and are highly sensitive to CD95 mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L. These data raise the intriguing possibility that CD95 could actually promote the growth of tumours through its nonapoptotic activities. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and c-Jun. These results demonstrate that CD95 plays a major growth promoting role during tumorigenesis and suggest that efforts to inhibit its activity rather than to enhance its activation should be considered during cancer therapy. There are 3 arrays for human ovarian cancer cell line, 2 arrays for human liver cancer cell line, and 2 arrays for mouse liver tissue. All the arrays are paired arrays with or without Fas knock-out.

2010-04-02 | E-GEOD-21154 | biostudies-arrayexpress

Expression data from mNSc after 48 hour of treatment with CD95L-T4

Project description:In neural stem cells, stimulation of the â??death receptorâ?? CD95 does not trigger apoptosis but resulted in increased stem cell survival and neuronal specification via activation of the Src /PI3K /AKT/mTOR signalling pathway. To further characterize CD95-dependent neural stem cell survival and differentiation we used conventional gene expression profiling combined with translation state array analysis. Mouse neural stem cells grown in neurosphere cultures were stimulated with a trimerized CD95L construct (CD95L-T4) and total as well as polysomal bound RNA was isolated 48 hours after stimulation and analysed by microarrays. CD95L-T4 treatment induced a global increase in ribosome-bound mRNA and protein translation as well as changes on genes involved in neurogenesis, protein synthesis and transcription factors. Mouse neural stem cells grown in neurosphere cultures were stimulated with a trimerized CD95L construct (CD95L-T4) and total as well as polysomal bound RNA was isolated 48 hours after stimulation and hybridized on affymetrix microarrays.

2010-03-09 | E-GEOD-15623 | biostudies-arrayexpress

CD95/Fas suppresses NF-B activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism

Project description:CD95 expression is preserved in triple-negative breast cancers (TNBCs) and CD95 loss in these cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2) using an unbiased proteomic approach. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit RelA (p65) and KPC1, which acts as E3 ubiquitin-protein ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines, that could account for the immune landscape remodeling in TNBC cells

2021-12-06 | PXD027196 | Pride

CD95L derived si- and shRNAs kill cancer cells through an RNAi mechanism by targeting survival genes [shL3.shR6.RNAseq.lg]

Project description:The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. However, most siRNAs or shRNAs targeting either CD95 or CD95L induce DICE (Death Induced by CD95/CD95L Elimination), a form of cell death in which a combination of different cell death pathways are activated, that is selective for transformed cells, and that preferentially affects cancer stem cells. We now provide evidence that both CD95 and CD95L are part of a network of genes that contain sequences that when expressed as either siRNAs or shRNAs are toxic to cancer cells. They act through canonical RNAi by targeting the 3'UTRs of critical survival genes. We propose that these embedded toxic sequences are part of a conserved mechanism that regulates cell death, and we predict the existence of endogenous siRNAs, that when produced, induce cell death to regulate genome fidelity. Our data have implications for cancer therapy and the use of RNAi.

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CD95L derived si- and shRNAs kill cancer cells through an RNAi mechanism by targeting survival genes [shL3.shR6.RNAseq.sm]

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CD95/Fas increases stemness in cancer cells by inducing a STAT1 dependent Type I interferon response [array]

Project description:CD95 was found to be important for both the formation of CSCs and their maintenance. Using a stable isotope labeling by amino acids in cell culture (SILAC) analysis we have now identified STAT1 as a critical gene that mediates the CSC-driving activity of CD95. We report that chronic stimulation of CD95 by either agonist antibodies, soluble CD95L or stably expressed membrane CD95L causes both serine and tyrosine phosphorylation of STAT1 and activation of STAT1 regulated genes. The genes most significantly induced were part of an interferon (IFN)-related DNA damage resistance signature (IRDS) recently identified in a radiation resistant squamous cell carcinoma cell line Nu61 when compared to parental SCC61 cells. The IRDS was found to strongly correlate with therapy resistance (chemotherapy and radiation) in multiple cancer cells as well as in 5 human primary cancers. We now report that CD95 stimulation of breast cancer cell lines or the SCC61 cells induces the upregulation of Type I IFNs that bind to both Type I receptors IFNAR1 and IFNR2 resulting in activation of JAK kinases, activation of STAT1 and induction of a number of STAT1-regulated genes. This process can be inhibited by active caspases. Consequently, we identified Type I IFNs as drivers of cancer stemness. Knockdown of STAT1 using either siRNAs or shRNAs, or deleting two independent sites in the STAT1 gene in MCF-7 cells using the CRIPSR/Cas9 gene editing system resulted in a loss of the ability of CD95 to increase stemness. This identifies STAT1 as a critical mediator of the CSCs-inducing activity of CD95.

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Expression data from mNSc after 48 hour of treatment with CD95L-T4

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