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Updated: Jul 5, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Heparan sulfate promotes TRAIL-induced tumor cell apoptosis
Yin Luo1, Huanmeng Hao1, Zhangjie Wang2
1Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, United States.
Abstract:
TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report, we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (KD = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL, and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.
Insights
Heparan sulfate (HS) enhances tumor cell apoptosis by promoting TRAIL oligomerization and DR5 internalization. HS expression levels correlate with TRAIL sensitivity, offering new therapeutic strategies.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of tumor cell apoptosis.
- Clinical trials for TRAIL-based therapies have been limited by tumor resistance and trial failures.
- The precise mechanisms regulating TRAIL efficacy remain incompletely understood.
Purpose of the Study:
- To investigate the role of heparan sulfate (HS) in regulating TRAIL-induced apoptosis.
- To elucidate the molecular interactions between TRAIL, HS, and death receptor 5 (DR5).
- To assess the potential of targeting TRAIL-HS interactions for cancer therapy.
Main Methods:
- Binding affinity assays to quantify TRAIL-HS interactions.
- Cell-based assays to measure TRAIL-induced apoptosis in cancer cells.
- Analysis of HS expression in myeloma cell lines.
- Co-immunoprecipitation and confocal microscopy to study protein complex formation.
Main Results:
- TRAIL binds to HS with high affinity, inducing higher-order oligomerization of TRAIL.
- Cell surface HS significantly promotes TRAIL-induced apoptosis in breast cancer and myeloma cells.
- HS expression levels inversely correlate with TRAIL resistance in myeloma cells.
- HS facilitates the formation of a ternary complex involving DR5 and TRAIL, promoting DR5 internalization.
Conclusions:
- Heparan sulfate is a critical regulator of TRAIL-induced apoptosis.
- TRAIL-HS interactions enhance TRAIL's apoptotic activity by promoting receptor complex formation and internalization.
- HS expression is a potential biomarker for TRAIL sensitivity.
- Targeting TRAIL-HS interactions may offer a promising strategy for improving TRAIL-based cancer therapies.
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