Abstract
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.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer death and is responsible for over 50,000 deaths annually in the United States [1]
Cells were not treated with any oxaliplatin in quantifying the level of Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) sensitization, and oxaliplatin was not supplemented in the cell culture media to exclude any possible effects from combination treatment
Our results demonstrate that OxR colorectal cancer cells are susceptible to TRAIL-mediated apoptosis
Summary
Colorectal cancer (CRC) is the second leading cause of cancer death and is responsible for over 50,000 deaths annually in the United States [1]. While surgery and radiation remain curative options for patients with localized disease, the standard of care for CRC patients with advanced metastatic disease is commonly combination front line chemotherapy treatment [4]. These chemotherapy regimens typically include fluorouracil (5-FU) and leucovorin (LV) in combination, which work together to inhibit DNA and RNA synthesis and modulate tumor growth, extending median survival in patients from 9 months (with palliative care) to over 12 months [5].
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