The tumor suppressive effect and apoptotic mechanism of TRAIL gene‐containing recombinant NDV in TRAIL‐resistant colorectal cancer HT‐29 cells and TRAIL‐nonresistant HCT116 cells, with each cell bearing a mouse model.

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Schematic representation of direct mechanisms of the rNDV‐TRAIL viruses. rNDV containing the TRAIL gene (rNDV‐TRAIL) can stably express the TRAIL gene. Also, rNDV‐TRAIL activates the NF‐кB pathway and induces the secretion of TRAIL. The expressed or induced TRAIL binds to the TRAIL receptor on DR4 or DR5. DR5 promotes TRAIL‐induced apoptotic pathways. The pro‐apoptotic complex is formed. Caspase 8 is cleaved, activates caspase 3, and triggers apoptosis via the extrinsic pathway. Also, caspase 8 induces an intrinsic pathway. The cytochrome C combines with procaspase‐9 to produce apoptosome. Apoptosome triggers caspase 9 followed by the activation of caspase‐3 which leads to ends up to apoptosis. [ABSTRACT FROM AUTHOR]