Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Death Receptors 4 and 5 (DR4/DR5) are key targets for cancer therapy, activating apoptosis via TNF-related apoptosis-inducing ligand (TRAIL).
• Tumor cells often exhibit resistance to TRAIL-induced apoptosis, with underlying mechanisms requiring further elucidation.
• Previous studies identified synthetic peptides (TRAILmim/DR5) that bind DR5 and induce apoptosis.

Purpose of the Study:

• To investigate the efficacy of a divalent form of TRAILmim/DR5 compared to TRAIL and anti-DR5 antibodies in inducing apoptosis in cancer cells.
• To explore the mechanisms of resistance and potential antagonism observed with TRAILmim/DR5.

Main Methods:

• Treatment of DR5-positive Jurkat, HCT116, and BJAB cells with hexameric TRAIL, divalent TRAILmim/DR5, and anti-DR5 agonist antibody.
• Assessment of apoptosis induction and sensitivity to cross-linking.
• Analysis of DR5 receptor internalization.

Main Results:

• Hexameric TRAIL effectively killed Jurkat and HCT116 cells; however, these cells were resistant to divalent TRAILmim/DR5 and poorly sensitive to anti-DR5 antibody.
• Cross-linking restored sensitivity to the anti-DR5 antibody but not to divalent TRAILmim/DR5.
• Divalent TRAILmim/DR5 induced apoptosis in BJAB cells but acted as an inhibitor of TRAIL-induced apoptosis in Jurkat and HCT116 cells.
• Rapid DR5 internalization upon treatment with divalent TRAILmim/DR5 was observed, potentially explaining its antagonist activity.

Conclusions:

• The efficacy of DR5-targeting agents is context-dependent, with divalent TRAILmim/DR5 exhibiting both agonist and antagonist activities.
• Tumor cell resistance to TRAIL-induced apoptosis involves complex mechanisms, including receptor internalization independent of apoptotic signaling.
• Further research is needed to optimize DR5-targeted cancer therapies and overcome resistance.