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Lewis glycosphingolipids as critical determinants of TRAIL sensitivity in cancer cells

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.

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Fig. 1: Lewis glycans promote TRAIL-induced apoptosis.
Fig. 2: Lewis glycans promote caspase 8 activation in Complex II.
Fig. 3: Lewis glycans are not detected on DR4 and DR5.
Fig. 4: Lewis glycans on glycoproteins do not affect TRAIL-induced apoptosis.
Fig. 5: Lewis glycans on glycolipids promote TRAIL-induced apoptosis.
Fig. 6: Positive correlation between expression of type I Lewis glycans and TRAIL sensitivity in colorectal cancer cell lines.
Fig. 7: Positive correlation between expression of type I Lewis glycans and TRAIL sensitivity in patient-derived colon cancer organoids.

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its supplementary information files. Data not included are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Ayaka Hiraishi for technical assistance.

Funding

This study was supported by the Japan Society for the Promotion of Science (KM: 16H06945 and 19K07399), the Takeda Science Foundation (KM), GSK Japan Research Grant 2020 (KM), and the Japan Agency for Medical Research and Development (JP20ae0101042 to KM and JP20gm1210002 to HN).

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KM conceived the project. TF, KM, and ST designed experiments. TF, KM, and ST performed experiments with assistance from JK, MS, and SK-S, AT and HK performed glycan structure analysis of DR4. MT-O and YM performed structural analysis of glycosphingolipids. TF, KM, ST, JK, YK, MI, KB, YM, KO, HN, and EM analyzed the data. TF and KM wrote the manuscript. KM and EM supervised the projects.

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Correspondence to Kenta Moriwaki or Eiji Miyoshi.

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Fukuoka, T., Moriwaki, K., Takamatsu, S. et al. Lewis glycosphingolipids as critical determinants of TRAIL sensitivity in cancer cells. Oncogene 41, 4385–4396 (2022). https://doi.org/10.1038/s41388-022-02434-3

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