Year: 2023
Type: preprint
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.
Source: eLife
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: U.S. Department of Energy, National Institutes of Health, Office of Science, University at Buffalo, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, Basic Energy Sciences, Biological and Environmental Research, Lawrence Berkeley National Laboratory
Awards: G1235180860, G140363568, G1756342139, G2123841078, G2202731092, A Pixel Array Detector System for Small Angle X-ray Scattering, G3217414483, G3258516066, G37370065, G3959563084, G4874579203, G572720644, G5885332871, G5959045253, G6093180023, G7374646816, G8229677252, G8898833266, G9000111321, G9000177019, G9000260527, G9000263589, The role of heparan sulfate in cathepsin K biology, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), Crystallographic studies of macromolecular structures
OpenAlex ID: W4390329047