Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization

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.

Automated summary

This study demonstrates that oxaliplatin-resistant CRC cells become more sensitive to TRAIL-mediated apoptosis due to increased DR4 expression, palmitoylation, and translocation. The alteration of DR4/raft colocalization and TRAIL sensitivity by raft perturbation via nystatin and resveratrol is significant. Additionally, treatment with TRAIL liposomes in blood samples from metastatic CRC patients results in a reduction of viable CTCs, with increased DR4/lipid raft colocalization corresponding to increased oxaliplatin resistance and efficacy of TRAIL liposomes.