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Relationship between the agonist activity of synthetic ligands of TRAIL-R2 and their cell surface binding modes
Neila Chekkat1, Caterina M Lombardo2,3, Cendrine Seguin1
1Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS, Université de Strasbourg, 67401 Illkirch, France.
Abstract:
Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL) appears as an interesting candidate for targeted cancer therapy as it induces apoptosis in cancer cells without toxicity to normal cells. TRAIL elicits apoptosis through agonist death receptor TRAIL-R1 and TRAIL-R2 engagement. Nevertheless, recombinant soluble TRAIL and monoclonal antibodies against these receptors demonstrated insufficient efficacy in clinical trials. This may be explained by the cell-type dependency of the apoptotic response, itself influenced by the effect on ligand binding mode of factors such as the level of receptor oligomerization or glycosylation. To investigate the relation between binding mode and signaling, we used previously described synthetic divalent and monovalent peptides specific for TRAIL-R2. We measured their pro-apoptotic activity on three cancer cell lines sensitive to rhTRAIL induced-apoptosis and monitored their cell-surface binding kinetics. The two divalent peptides bound with strong affinity to TRAIL-R2 expressed on B lymphoma BJAB cells and induced a high degree of apoptosis. By contrast, the same peptides bound weakly to TRAIL-R2 expressed at the surface of the human colon cancer HCT116 or T lymphoma Jurkat cell lines and did not induce their apoptosis. Cross-linking experiments suggest that these differences could be afforded by variations in the TRAIL-R2 oligomerization state at cell surface before ligand addition. Moreover divalent peptides showed a different efficiency in BJAB apoptosis induction, and kinetic distribution analysis of the BJAB binding curves suggested subtle differences in binding mechanisms. Thus our data support a relation between the cell-surface binding mode of the peptides and their pro-apoptotic activity. In this case the precise characterization of ligand binding to the surface of living cells would be predictive of the therapeutic potential of TRAIL-R2 synthetic ligands prior to clinical trials.
Insights
Synthetic peptides targeting Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL)-R2 show promise for cancer therapy. Their binding mode to cancer cells, influenced by receptor state, predicts pro-apoptotic activity, potentially guiding future TRAIL-based treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL) is a potential cancer therapeutic agent inducing apoptosis in cancer cells.
- Clinical trials of recombinant TRAIL and anti-TRAIL receptor antibodies showed limited efficacy, possibly due to cell-type-dependent responses and ligand-receptor interactions.
- Factors like receptor oligomerization and glycosylation may influence TRAIL's binding mode and subsequent apoptotic signaling.
Purpose of the Study:
- To investigate the relationship between the binding mode of synthetic TRAIL-R2 specific peptides and their pro-apoptotic activity.
- To explore how cell-surface TRAIL-R2 characteristics influence the efficacy of TRAIL-based therapeutics.
Main Methods:
- Utilized synthetic divalent and monovalent peptides targeting TRAIL-R2.
- Assessed pro-apoptotic activity on three cancer cell lines (BJAB, HCT116, Jurkat) sensitive to TRAIL.
- Monitored cell-surface binding kinetics and receptor-ligand interactions using cross-linking experiments.
Main Results:
- Divalent peptides exhibited high affinity binding to TRAIL-R2 on BJAB cells, inducing significant apoptosis.
- Weak binding and no apoptosis induction were observed with the same peptides on HCT116 and Jurkat cells.
- Cross-linking experiments suggested differences in TRAIL-R2 oligomerization states on cell surfaces contributed to varied responses.
- Kinetic analysis indicated subtle differences in binding mechanisms for divalent peptides on BJAB cells.
Conclusions:
- A correlation exists between the cell-surface binding mode of TRAIL-R2 peptides and their pro-apoptotic efficacy.
- Cell-surface receptor characteristics, such as oligomerization state, significantly impact therapeutic response.
- Characterizing ligand binding to cell-surface receptors is crucial for predicting the therapeutic potential of synthetic TRAIL-R2 ligands before clinical application.
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