RT Journal Article
SR Electronic
T1 Oxaliplatin Resistance in Colorectal Cancer Enhances TRAIL Sensitivity Via Death Receptor 4 Upregulation and Lipid Raft Localization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.05.434100
DO 10.1101/2021.03.05.434100
A1 Greenlee, Joshua D.
A1 Cavestany, Maria Lopez
A1 Ortiz-Otero, Nerymar
A1 Liu, Kevin
A1 Subramanian, Tejas
A1 Cagir, Burt
A1 King, Michael R.
YR 2021
UL http://biorxiv.org/content/early/2021/03/05/2021.03.05.434100.abstract
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.