Vanderbilt University, Department of Biomedical Engineering PMB, Nashville, United States.
Donald Guthrie Foundation (DGF) for Research and Education Sayre, Sayre, United States.
Elife. 2021 Aug 3;10:e67750. doi: 10.7554/eLife.67750.
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.
结直肠癌（CRC）仍然是癌症死亡的主要原因，其死亡率与转移和化疗耐药有关。我们证明，奥沙利铂耐药的 CRC 细胞对 TRAIL 介导的细胞凋亡敏感。奥沙利铂耐药细胞中 caspase-10 的转录下调，但在亲本细胞中用 CRISPR-Cas9 缺失 caspase-10 后，对 TRAIL 敏感性的影响很小。在奥沙利铂耐药细胞中发现的敏化作用是由于 DR4 的增加，以及 DR4 的棕榈酰化和向脂筏的易位显著增强所致。通过制霉菌素和白藜芦醇对筏进行扰动，显著改变了 DR4/筏的共定位和 TRAIL 的敏感性。用 TRAIL 脂质体处理转移性 CRC 患者的血液样本，观察到存活的循环肿瘤细胞（CTC）减少了 57%。发现在 CTC 中 DR4/脂筏的共定位增加与奥沙利铂耐药性增加以及 TRAIL 脂质体的疗效增加相对应。据我们所知，这是第一项研究原发性 CTC 中脂筏作用的研究。
