PT - JOURNAL ARTICLE AU - Greenlee, Joshua D. AU - Cavestany, Maria Lopez AU - Ortiz-Otero, Nerymar AU - Liu, Kevin AU - Subramanian, Tejas AU - Cagir, Burt AU - King, Michael R. TI - Oxaliplatin Resistance in Colorectal Cancer Enhances TRAIL Sensitivity Via Death Receptor 4 Upregulation and Lipid Raft Localization AID - 10.1101/2021.03.05.434100 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.03.05.434100 4099 - http://biorxiv.org/content/early/2021/03/05/2021.03.05.434100.short 4100 - http://biorxiv.org/content/early/2021/03/05/2021.03.05.434100.full AB - 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.Significance Oxaliplatin-resistant colorectal cancer cells show increased sensitivity to apoptosis via TRAIL. This study shows that this is due to death receptor 4 localization to lipid rafts.