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

eLife

Burt Cagir¹  Michael R King²  Tejas Subramanian²  Kevin Liu²  Joshua D Greenlee²  Maria Lopez-Cavestany²  Nerymar Ortiz-Otero² 

[1] Donald Guthrie Foundation (DGF) for Research and Education Sayre, Sayre, United States;Vanderbilt University, Department of Biomedical Engineering PMB, Nashville, United States;

关键词: lipid rafts;    metastasis;    TRAIL;    death receptors;    palmitoylation;    Human;   

DOI  :  10.7554/eLife.67750

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY