Libentech Co. LTD, Daejeon, Republic of Korea.
Graduate School of Medical Science, College of medicine, Yonsei University, Seoul, Republic of Korea.
Cancer Med. 2023 Oct;12(20):20380-20395. doi: 10.1002/cam4.6622. Epub 2023 Oct 16.
TRAIL is an anticancer drug that induces cancer cell apoptosis by interacting with death receptors (DRs). However, owing to low cell-surface expression of DRs, certain colorectal cancer (CRC) cells resist TRAIL-induced apoptosis. Newcastle disease virus (NDV) infection can elevate DR protein expression in cancer cells, potentially influencing their TRAIL sensitivity. However, the precise mechanism by which NDV infection modulates DR expression and impacts TRAIL sensitivity in cancer cells remains unknown.
Herein, we developed nonpathogenic NDV VG/GA strain-based recombinant NDV (rNDV) and TRAIL gene-containing rNDV (rNDV-TRAIL). We observed that viral infections lead to increased DR and TRAIL expressions and activate signaling proteins involved in intrinsic and extrinsic apoptosis pathways. Experiments were conducted in vitro using TRAIL-resistant CRC cells (HT-29) and nonresistant CRC cells (HCT116) and in vivo using relevant mouse models.
rNDV-TRAIL was found to exhibit better apoptotic efficacy than rNDV in CRC cells. Notably, rNDV-TRAIL had the stronger cancer cell-killing effect in TRAIL-resistant CRC cells. Western blot analyses showed that both rNDV and rNDV-TRAIL infections activate signaling proteins involved in the intrinsic and extrinsic apoptotic pathways. Notably, rNDV-TRAIL promotes concurrent intrinsic and extrinsic signal transduction in both HCT-116 and HT-29 cells.
Therefore, rNDV-TRAIL infection effectively enhances DR expression in DR-depressed HT-29 cells. Moreover, the TRAIL protein expressed by rNDV-TRAIL effectively interacts with DR, leading to enhanced apoptosis in TRAIL-resistant HT-29 cells. Therefore, rNDV-TRAIL has potential as a promising therapeutic approach for treating TRAIL-resistant cancers.
TRAIL 是一种抗癌药物，通过与死亡受体（DRs）相互作用诱导癌细胞凋亡。然而，由于某些结直肠癌（CRC）细胞表面 DRs 的表达较低，它们抵抗 TRAIL 诱导的凋亡。新城疫病毒（NDV）感染可以提高癌细胞中 DR 蛋白的表达，可能影响其对 TRAIL 的敏感性。然而，NDV 感染调节 DR 表达并影响癌细胞中 TRAIL 敏感性的确切机制尚不清楚。
在此，我们开发了基于非致病性 NDV VG/GA 株的重组 NDV（rNDV）和含有 TRAIL 基因的 rNDV（rNDV-TRAIL）。我们观察到病毒感染导致 DR 和 TRAIL 表达增加，并激活参与内在和外在凋亡途径的信号蛋白。在体外使用 TRAIL 耐药的 CRC 细胞（HT-29）和非耐药的 CRC 细胞（HCT116）以及相关的小鼠模型进行实验。
rNDV-TRAIL 被发现比 rNDV 在 CRC 细胞中具有更好的促凋亡效果。值得注意的是，rNDV-TRAIL 在 TRAIL 耐药的 CRC 细胞中具有更强的杀伤癌细胞的作用。Western blot 分析表明，rNDV 和 rNDV-TRAIL 感染均可激活参与内在和外在凋亡途径的信号蛋白。值得注意的是，rNDV-TRAIL 可促进 HCT-116 和 HT-29 细胞中内在和外在信号的同时转导。
因此，rNDV-TRAIL 感染可有效增强 DR 表达低下的 HT-29 细胞中的 DR 表达。此外，rNDV-TRAIL 表达的 TRAIL 蛋白可有效与 DR 相互作用，从而增强 TRAIL 耐药的 HT-29 细胞的凋亡。因此，rNDV-TRAIL 具有作为治疗 TRAIL 耐药癌症的有前途的治疗方法的潜力。
