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 o...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-08-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67750 |
| _version_ | 1811202553424117760 |
|---|---|
| author | Joshua D Greenlee Maria Lopez-Cavestany Nerymar Ortiz-Otero Kevin Liu Tejas Subramanian Burt Cagir Michael R King |
| author_facet | Joshua D Greenlee Maria Lopez-Cavestany Nerymar Ortiz-Otero Kevin Liu Tejas Subramanian Burt Cagir Michael R King |
| author_sort | Joshua D Greenlee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:41:58Z |
| format | Article |
| id | doaj.art-5276184522204b4b8306233e253f5fd0 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:41:58Z |
| publishDate | 2021-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5276184522204b4b8306233e253f5fd02022-12-22T03:51:18ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.67750Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localizationJoshua D Greenlee0https://orcid.org/0000-0002-1088-727XMaria Lopez-Cavestany1https://orcid.org/0000-0001-5358-3746Nerymar Ortiz-Otero2Kevin Liu3Tejas Subramanian4Burt Cagir5https://orcid.org/0000-0002-9682-3807Michael R King6https://orcid.org/0000-0002-0223-7808Vanderbilt University, Department of Biomedical Engineering PMB, Nashville, United StatesVanderbilt University, Department of Biomedical Engineering PMB, Nashville, United StatesVanderbilt University, Department of Biomedical Engineering PMB, Nashville, United StatesVanderbilt University, Department of Biomedical Engineering PMB, Nashville, United StatesVanderbilt University, Department of Biomedical Engineering PMB, Nashville, United StatesDonald Guthrie Foundation (DGF) for Research and Education Sayre, Sayre, United StatesVanderbilt University, Department of Biomedical Engineering PMB, Nashville, United StatesColorectal 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.https://elifesciences.org/articles/67750lipid raftsmetastasisTRAILdeath receptorspalmitoylation |
| spellingShingle | Joshua D Greenlee Maria Lopez-Cavestany Nerymar Ortiz-Otero Kevin Liu Tejas Subramanian Burt Cagir Michael R King Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization eLife lipid rafts metastasis TRAIL death receptors palmitoylation |
| title | Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization |
| title_full | Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization |
| title_fullStr | Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization |
| title_full_unstemmed | Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization |
| title_short | Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization |
| title_sort | oxaliplatin resistance in colorectal cancer enhances trail sensitivity via death receptor 4 upregulation and lipid raft localization |
| topic | lipid rafts metastasis TRAIL death receptors palmitoylation |
| url | https://elifesciences.org/articles/67750 |
| work_keys_str_mv | AT joshuadgreenlee oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization AT marialopezcavestany oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization AT nerymarortizotero oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization AT kevinliu oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization AT tejassubramanian oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization AT burtcagir oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization AT michaelrking oxaliplatinresistanceincolorectalcancerenhancestrailsensitivityviadeathreceptor4upregulationandlipidraftlocalization |