Abstract
CD95/Fas is an apoptosis inducing death receptor. However, it also has multiple nonapoptotic activities that are tumorigenic. Chronic stimulation of CD95 on breast cancer cells can increase their cancer initiating capacity through activation of a type I interferon (IFN-I)/STAT1 pathway when caspases are inhibited. We now show that this activity relies on the canonical components of the CD95 death-inducing signaling complex, FADD and caspase-8, and on the activation of NF-κB. We identified caspase-2 as the antagonistic caspase that downregulates IFN-I production. Once produced, IFN-Is bind to their receptors activating both STAT1 and STAT2 resulting in upregulation of the double stranded (ds)RNA sensor proteins RIG-I and MDA5, and a release of a subset of endogenous retroviruses. Thus, CD95 is part of a complex cell autonomous regulatory network that involves activation of innate immune components that drive cancer stemness and contribute to therapy resistance.
Highlights
CD95/Fas is an apoptosis inducing death receptor
The lack of CD95 expression had no effect on the activation of STAT1 in cells treated with IFNβ (Fig. 1C and Fig. S1C, right panel), which by-passes the requirement for CD95 stimulation, confirming that IFNR signaling to STAT1 is downstream of CD95
The data suggest that the increased cancer stemness seen in cells stimulated through CD95 is dependent on the expression of the two main death inducing signaling complex (DISC) components FADD and caspase-8
Summary
CD95/Fas is an apoptosis inducing death receptor. it has multiple nonapoptotic activities that are tumorigenic. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA5) are soluble receptors that sense dsRNAs of different lengths[14]. They both interact with the mitochondrial signaling adaptor MAVS. It was demonstrated that ERVs could be mobilized by treating cancer cells with DNA methyltransferase (DNMT) inhibitors resulting in the activation of the dsRNA sensors MDA5 and TLR316,17. This viral RNA sensing mechanism is often viewed as antiproliferative and in many cases to induce apoptosis or other forms of cell death[18]. In the context of breast cancer we found that treating cancer cells directly with IFN-I increased their stemness and the frequency of cancer initiating cells (CICs) in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
