TRAIL induces apoptosis but not necroptosis in colorectal and pancreatic cancer cells preferentially via the TRAIL-R2/DR5 receptor

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1865; no. 3; pp. 522 - 531
• Main Authors: Nahacka, Zuzana, Svadlenka, Jan, Peterka, Martin, Ksandrova, Marie, Benesova, Simona, Neuzil, Jiri, Andera, Ladislav
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2018
• Subjects: Apoptosis; Apoptosis - genetics; Cancer; Caspase 8 - genetics; Cell Proliferation - genetics; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Necroptosis; Necrosis - genetics; Necrosis - pathology; NF-kappa B - genetics; Pancreas - metabolism; Pancreas - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Receptor-specific signaling; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; RNA, Small Interfering; Signal Transduction - genetics; TNF-Related Apoptosis-Inducing Ligand - genetics; TRAIL; Receptor-specific signaling; TRAIL; Necroptosis; Apoptosis; Cancer
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2017.12.006

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that can trigger apoptosis in many types of human cancer cells via engagement of its two pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). TRAIL can also activate several other signaling pathways such as activation of stress kinases, canonical NF-κB signaling and necroptosis. Though both receptors are ubiquitously expressed, their relative participation in TRAIL-induced signaling is still largely unknown. To analyze TRAIL receptor-specific signaling, we prepared Strep-tagged, trimerized variants of recombinant human TRAIL with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, we examined the contribution of individual pro-apoptotic receptors to TRAIL-induced signaling pathways. We found that in TRAIL-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeds comparably via both DR4- and DR5-activated signaling. TRAIL-induced apoptosis, enhanced by the inhibitor of the Bcl-2 family ABT-737, or by the translation inhibitor homoharringtonine, proceeded in both cell lines predominantly via the DR5 receptor. ShRNA-mediated downregulation of DR4 or DR5 receptors in HT-29 cells also pointed to a stronger contribution of DR5 in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was activated similarly by both DR4- or DR5-specific ligands. Activation of auxiliary signaling pathways involving NF-κB or stress kinases proceeded under apoptotic conditions mainly in a DR5-dependent manner, while these signaling pathways were during necroptosis similarly activated by either of these ligands. Our study provides the first systematic insight into DR4−/DR5-specific signaling in colorectal and pancreatic cancer cells.
•DR5-selective ligands are superior to DR4-selective ligand in triggering apoptosis in colorectal and pancreatic cancer cells.•DR5-triggered enhanced activation of stress kinases can contribute to pro-apoptotic signaling.•In contrast to the induction of apoptosis, the necroptotic signaling is similarly activated by DR4- or DR5-specific ligands.