A research from C Geismann and F Grohmann shows that c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells.

 In their cell-based models of Pancreatic ductal adenocarcinoma (PDAC), they were able to show for the first time that c-Rel is a central mediator of an antiapoptotic signalling pathway protecting from TRAIL-induced apoptosis. By siRNA-mediated downregulation of c-Rel expression, they were able to show that c-Rel is part of the NF-κB complex induced by TRAIL and conferring apoptosis resistance to an extent similar to other NF-κB family members.

As initially shown by array analysis and later confirmed by qPCR and EMSA, c-Rel induces the expression of the transcription factor NFATc2 in TRAIL-resistant PDAC cell lines. SiRNA-mediated downregulation of either c-Rel or NFATc2 significantly sensitized PDAC cell lines to TRAIL-induced apoptosis and abolished the induction of COX-2 expression by TRAIL in these cell lines. In line with this, pharmacologic inhibition of COX-2 by celecoxib greatly sensitized the PDAC cell lines in an extent similar to c-Rel or NFATc2 inhibition.

Notably, unlike a recent study showing comparable effects of c-Rel on the apoptotic response in head and neck cancer, they did not observe any changes in proapoptotic genes such as PUMA or p21 in the array analysis. In contrast to reports indicating a proapoptotic function of c-Rel, they clearly established an antiapoptotic effect of c-Rel in TRAIL-resistant PDAC cell lines.