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

0503426 - ÚMG 2019 RIV NL eng J - Journal Article
Nahácka, Zuzana - Švadlenka, Jan - Peterka, Martin - Ksandrova, Marie - Benešová, Simona - Neuzil, J. - Anděra, Ladislav
TRAIL induces apoptosis but not necroptosis in colorectal and pancreatic cancer cells preferentially via the TRAIL-R2/DR5 receptor.
Biochimica Et Biophysica Acta-Molecular Cell Research. Roč. 1865, č. 3 (2018), s. 522-531. ISSN 0167-4889. E-ISSN 1879-2596
R&D Projects: GA MŠMT LH12202; GA ČR GA15-03379S; GA ČR(CZ) GA15-14789S; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:68378050
Keywords : trail * Apoptosis * Necroptosis * Receptor-specific signaling * Cancer
OECD category: Biochemistry and molecular biology
Impact factor: 4.739, year: 2018

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-KB 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-xB 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.
Permanent Link: http://hdl.handle.net/11104/0295343