Trail sensitivity in Ewing's sarcoma patients is modulated by the expression of death receptor 4 and its short isoform despite predominant dr5 level

Colorectal cancer (CRC) remains a leading cause of cancer death, and its mortality is associated with metastasis and chemoresistance. We demonstrate that oxaliplatin-resistant CRC cells are sensitized to TRAIL-mediated apoptosis. Oxaliplatin-resistant cells exhibited transcriptional downregulation of caspase-10, but this had minimal effects on TRAIL sensitivity following CRISPR-Cas9 deletion of caspase-10 in parental cells. Sensitization effects in oxaliplatin-resistant cells were found to be a result of increased DR4, as well as significantly enhanced DR4 palmitoylation and translocation into lipid rafts. Raft perturbation via nystatin and resveratrol significantly altered DR4/raft colocalization and TRAIL sensitivity. Blood samples from metastatic CRC patients were treated with TRAIL liposomes, and a 57% reduction of viable circulating tumor cells (CTCs) was observed. Increased DR4/lipid raft colocalization in CTCs was found to correspond with increased oxaliplatin resistance and increased efficacy of TRAIL liposomes. To our knowledge, this is the first study to investigate the role of lipid rafts in primary CTCs.

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Abstract 2917: Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma

10.1158/1538-7445.am2015-2917 ◽

2015 ◽

Author(s):

Zhigang Kang ◽

D Seth Goldstein ◽

Yunkai Yu ◽

Paul S. Meltzer ◽

David M. Loeb ◽

...

Keyword(s):

Ewing’S Sarcoma ◽

Tumor Response ◽

Ewing's Sarcoma ◽

Death Receptor ◽

Caspase 8 ◽

Death Receptor 5 ◽

Agonist Antibody

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Fenretinide-dependent upregulation of death receptors through ASK1 and p38α enhances death receptor ligand-induced cell death in Ewing's sarcoma family of tumours

British Journal of Cancer ◽

10.1038/sj.bjc.6605896 ◽

2010 ◽

Vol 103 (9) ◽

pp. 1380-1390 ◽

Cited By ~ 12

Author(s):

D E White ◽

S A Burchill

Keyword(s):

Cell Death ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Death Receptor ◽

Death Receptors ◽

Receptor Ligand ◽

Death Receptor Ligand

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Oxaliplatin Resistance in Colorectal Cancer Enhances TRAIL Sensitivity Via Death Receptor 4 Upregulation and Lipid Raft Localization

10.1101/2021.03.05.434100 ◽

2021 ◽

Author(s):

Joshua D. Greenlee ◽

Maria Lopez Cavestany ◽

Nerymar Ortiz-Otero ◽

Kevin Liu ◽

Tejas Subramanian ◽

...

Keyword(s):

Colorectal Cancer ◽

Lipid Rafts ◽

Lipid Raft ◽

Death Receptor ◽

Chemotherapy Treatment ◽

Death Receptor 4 ◽

Trail Sensitivity ◽

Resistance To Chemotherapy ◽

Over Time

Colorectal cancer (CRC) remains a leading cause of cancer death, and its mortality is associated with metastasis and resistance to chemotherapy. We demonstrate that oxaliplatin-resistant (OxR) CRC cells are sensitized to TRAIL-mediated apoptosis. Oxaliplatin-resistant cells exhibited transcriptional downregulation of caspase-10, but this effect was of little consequence to TRAIL sensitivity following CRISPR-Cas9 depletion of caspase-10. OxR cells were found to have increased expression of DR4, as well as significantly enhanced DR4 palmitoylation and translocation into lipid rafts. Raft perturbation via nystatin and resveratrol significantly altered DR4/raft colocalization and TRAIL sensitivity. Blood samples from metastatic CRC patients were treated with TRAIL liposomes, and a 57% reduction of viable circulating tumor cells (CTCs) was observed. The degree of DR4/lipid raft colocalization in CTCs was found to increase over time in patients receiving chemotherapy treatment. To our knowledge, this is the first study to investigate the role of lipid rafts in primary CTCs.

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