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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
The relevance of NF-kappaB for CD95 signaling in tumor cells
Patrick Legembre1, Bryan C Barnhart, Marcus E Peter
1The Ben May Institute for Cancer Research, Committees on Immunology and Cancer Biology, The University of Chicago, Chicago, Illinios 60637, USA.
Abstract:
Most members of the death receptor family including CD95 (APO-1/Fas) have been shown to induce both apoptosis as well as non-apoptotic pathways depending on the tissue and the circumstances. One of the non-apoptotic pathways emanating from CD95, activation of NF-kappaB, has recently been demonstrated to regulate invasiveness of apoptosis resistant tumor cells. In contrast, activation of NF-kappaB in apoptosing cells is believed to be suppressed due to cleavage of various NF-kappaB pathway components by active caspases that execute apoptosis. We now present data demonstrating that in certain highly CD95 apoptosis sensitive cells NF-kappaB is robustly activated. In fact overexpression of apoptosis inhibitors such as Bcl-2 or c-FLIPL in these cells results in decreased activation of NF-kappaB through CD95. We propose a model in which NF-kappaB is generally activated in certain cells but may have different functions depending on whether cells are programmed to die or to survive.
Insights
CD95 receptor activation can trigger NF-kappaB, a transcription factor, in apoptosis-sensitive cells. This challenges the idea that caspases suppress NF-kappaB during apoptosis.
Area of Science:
- Cellular biology
- Molecular signaling
- Cancer research
Background:
- Death receptors, including CD95 (APO-1/Fas), initiate apoptosis and non-apoptotic pathways.
- CD95-mediated NF-kappaB activation is linked to tumor cell invasiveness, but typically suppressed during apoptosis.
- Caspase activity during apoptosis is thought to inhibit NF-kappaB pathway components.
Purpose of the Study:
- To investigate NF-kappaB activation in CD95-mediated apoptosis.
- To explore the role of apoptosis inhibitors in CD95-induced NF-kappaB signaling.
- To propose a model for context-dependent NF-kappaB function.
Main Methods:
- Utilized CD95-expressing cells with varying apoptosis sensitivities.
- Overexpressed apoptosis inhibitors like Bcl-2 and c-FLIPL.
- Assessed NF-kappaB activation through CD95 stimulation.
Main Results:
- Demonstrated robust NF-kappaB activation in highly CD95 apoptosis-sensitive cells.
- Showed that overexpressing apoptosis inhibitors (Bcl-2, c-FLIPL) decreased CD95-induced NF-kappaB activation.
- Indicated a potential inverse relationship between apoptosis execution and NF-kappaB activation in these cells.
Conclusions:
- NF-kappaB can be robustly activated in CD95-sensitive cells, contrary to prevailing assumptions.
- Apoptosis inhibitors modulate CD95-mediated NF-kappaB activation.
- A model is proposed where NF-kappaB function is context-dependent on cell fate (survival vs. apoptosis).
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