Icariin sensitizes human colon cancer cells to TRAIL-induced apoptosis via ERK-mediated upregulation of death receptors

Abstract

Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) is considered to be a potential therapeutic target for various types of cancer. However, colon cancer is difficult to treat due to its resistance to TRAIL. Therefore, various trials have been conducted to overcome TRAIL resistance in colon cancer. The present study aimed to determine whether icariin (ICA) may sensitize human colon cancer cells to TRAIL-induced apoptosis in vitro and in vivo. In the investigation of the effect of ICA on TRAIL-induced apoptosis, the LIVE/DEAD assay results demonstrated that TRAIL plus ICA synergistically induced apoptosis in 49% of HCT116 colon cancer cells. These results were confirmed using long-term colony formation assay. ICA potentiated TRAIL-induced apoptosis by modulating the expression of apoptotic proteins and the induction of cell surface death receptors (DRs) 4 and 5. Upregulation of DRs by ICA was also observed at the transcriptional level by RT-PCR. The expression of DR by ICA was increased through the production of reactive oxygen species (ROS). The results also suggested that increased expression of DR by ICA may be due to the activation of ERK and induction of the transcription factor CCAAT enhancer-binding protein homologous protein (CHOP). NAC, a ROS scavenger, reduced the effect of ICA on ERK activation, DR induction and sensitization of TRAIL-induced apoptosis. In addition, ICA enhanced the effects of TRAIL to reduce tumor growth in an in vivo xenograft mouse model. Overall, the present study provided evidence that ICA sensitized tumor cells to TRAIL-induced apoptosis via ROS-, ERK- and CHOP-mediated upregulation of DR5 and DR4. Based on these results, it is suggested that the antitumor activity of ICA and TRAIL co-treatment in vitro and in vivo may be used as an effective therapeutic agent in chemotherapy.