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Lewis glycosphingolipids as critical determinants of TRAIL sensitivity in cancer cells
Tomoya Fukuoka1,2, Kenta Moriwaki3, Shinji Takamatsu1
1Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death and contributes to tumor rejection by cytotoxic lymphocytes in cancer immunosurveillance and immunotherapy. TRAIL and TRAIL receptor agonists have garnered wide popularity as promising agents for cancer therapy. We previously demonstrated that the loss of fucosylation in cancer cells impairs TRAIL sensitivity; however, the precise structures of the fucosylated glycans that regulate TRAIL sensitivity and their carrier molecules remain elusive. Herein, we observed that Lewis glycans among various fucosylated glycans positively regulate TRAIL-induced cell death. Specifically, Lewis glycans on lacto/neolacto glycosphingolipids, but not glycoproteins including TRAIL receptors, enhanced TRAIL-induced formation of the cytosolic caspase 8 complex, without affecting the formation of the membranous receptor complex. Furthermore, type I Lewis glycan expression in colon cancer cell lines and patient-derived cancer organoids was positively correlated with TRAIL sensitivity. These findings provide novel insights into the regulatory mechanism of TRAIL-induced cell death and facilitate the identification of novel predictive biomarkers for TRAIL-related cancer therapies in future.
Insights
Lewis glycans on cancer cells enhance sensitivity to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) therapy. This discovery offers potential biomarkers for predicting patient response to TRAIL-based cancer treatments.
Area of Science:
- Cancer biology
- Glycobiology
- Immunology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is crucial for cancer cell death and immune surveillance.
- TRAIL-based therapies show promise for cancer treatment, but sensitivity varies.
- Previous work indicated impaired TRAIL sensitivity due to loss of fucosylation in cancer cells.
Purpose of the Study:
- To identify specific fucosylated glycans and their carrier molecules that regulate TRAIL sensitivity.
- To elucidate the mechanism by which these glycans influence TRAIL-induced apoptosis.
Main Methods:
- Analysis of various fucosylated glycans in cancer cells.
- Investigating the effect of Lewis glycans on TRAIL-induced caspase 8 complex formation.
- Correlating type I Lewis glycan expression with TRAIL sensitivity in colon cancer models.
Main Results:
- Lewis glycans, specifically on lacto/neolacto glycosphingolipids, were found to positively regulate TRAIL-induced cell death.
- These glycans enhanced the formation of the cytosolic caspase 8 complex, independent of TRAIL receptor complex formation.
- A positive correlation was observed between type I Lewis glycan expression and TRAIL sensitivity in colon cancer cell lines and patient organoids.
Conclusions:
- Lewis glycans on glycosphingolipids are key regulators of TRAIL sensitivity.
- These findings reveal a novel mechanism for TRAIL-induced apoptosis.
- Type I Lewis glycans may serve as predictive biomarkers for TRAIL-based cancer therapies.
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