Impact of death receptor signaling on the malignancy of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma, PDAC, is a type of tumor with late diagnosis, rapid progression and poor prognosis. It is mostly unresponsive to chemo- and radiation therapy due to a marked resistance against apoptosis induction via both the intrinsic and extrinsic pathway. Accordingly, also activation of death receptors of the TNF-receptor superfamily does not or hardly induces apoptosis in PDAC cells. The reasons for this resistance include expression of multiple inhibitory proteins that block apoptotic signaling at almost every step of the signaling cascade. Moreover and more importantly, death receptors such as CD95/Fas, TRAIL-R1/-R2 and TNF-R1 exhibit marked non-apoptotic functions after ligand binding leading to strong proinflammatory responses, which contribute to survival, proliferation, migration and invasion, causing an even more pronounced malignant phenotype. This non-apoptotic signal transduction is facilitated via distinct adapter proteins, such as TRAF2 that bind to death receptor complexes and stimulate proinflammatory signal pathways leading to activation of NF-κB and AP-1 transcription factors. Therapeutic interventions in oncology utilizing death ligands, e.g. TRAIL, or triggering death receptors indirectly, must be carefully evaluated with respect to possible "side effects" and should be designed in a way counteracting non-apoptotic proinflammatory signaling.