TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5

Abstract

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF-kappaB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.

Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines

“…DAPI staining validates increased induction of apoptosis after combined treatment especially with 15d-PGJ 2 in parental and drug-resistant HEYs with exception of the partial TRAIL-resistant docetaxel-resistant and the TRAIL-resistant control cells be accomplished by the gemcitabine-resistant subclone that showed stronger expression of DR4 compared to DR5 indicating that apoptosis is most likely induced via DR4 in these TRAIL-sensitive cells. Recently, a higher sensitivity to TRAIL was addressed to a higher expression of DR4 in colon cancer and pancreatic tumor cells (Sussman et al 2007;Lemke et al 2010). The lack of correlation between the expression of death and decoy receptors and the sensitivity of the various HEY subclones may be explained by an autocrine production of a soluble decoy receptor by resistant cells, e. g., osteoprotegerin (OPG), a member of the TNF receptor family, that competes for TRAIL binding providing a mechanism for protection against apoptosis.…”

Death Receptor-Ligand Systems in Cancer, Cell Death, and Inflammation

“…TRAIL and CD95L cannot only induce apoptosis but also proinflammatory, proliferative, and promigratory signals (Ehrhardt et al 2003;Budd et al 2006;Peter et al 2007;Wilson et al 2009;Lemke et al 2010;Roder et al 2011). Some of these signals occur in a FADD/caspase-8-independent manner but the mechanisms are still debated (Green 2010).…”

TRAIL-engineered pancreas-derived mesenchymal stem cells: characterization and cytotoxic effects on pancreatic cancer cells

“…32,33 Increased number of MSC-mediated anticancer studies have shown MSCs to be an effective therapeutic tool and gene carrier for the treatment of pancreatic cancer. 34 To use MSCs as effective anticancer agent vehicles, we need a viable and practical source of MSCs and a method to successfully transfect MSCs with anticancer genes.…”