The relevance of NF-kappaB for CD95 signaling in tumor cells.

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.