Formosanin C Induces ROS/p38-Mediated Cell Death While Also Promoting Protective Autophagy in Pancreatic Cancer

PDAC, also known as pancreatic ductal adenocarcinoma, is a highly aggressive form of cancer that currently lacks efficient treatment options. Formosanin C (FC) has been found to have pharmacological activities in the treatment of inflammation and cancer in modern pharmacological studies. It remains unclear whether FC is effective against PDAC. The aim of this study is to evaluate the effects of FC on PDAC and to explore the underlying mechanisms. Cell proliferation was measured using CCK8, colony formation, EDU incorporation, and cell cycle assays. Apoptosis was assessed via Annexin V-FITC/PI staining. Reactive oxygen species (ROS) were determined using the DCFH-DA probe. Protein expressions were determined by Western blot and immunocytochemistry. The xenograft model was used to evaluate in vivo antitumorigenic activities. FC suppressed cell growth and caused DNA damage in PDAC cells. Apparent apoptosis occurred in the FC-treated cells, which was associated with enhanced endoplasmic reticulum (ER) stress. FC significantly induced ROS generation in PDAC cells. Further analyses showed that ROS are pivotal for the FC-induced cell death. Furthermore, ROS-induced p38 activation was also accountable for cell death initiated by FC. Interestingly, FC also induced a cytoprotective autophagy in PDAC cells; blocking autophagy further enhanced the inhibited cell proliferation. Experiments conducted in living organisms demonstrated that FC inhibited the proliferation of PDAC tumors in mice. FC suppresses PDAC tumor growth through ROS/p38-mediated cell death. FC also stimulates a cytoprotective autophagy. This study will provide new ideas for PDAC treatment.