Corynoxine Exerts Inhibitory Effects on Pancreatic Cancer by Inducing Endoplasmic Reticulum Stress-Mediated Apoptosis Via ROS-p38 Pathway

Background: Pancreatic cancer is one of the most malignant tumors, and effective therapeutic strategies are still lacking. While Corynoxine (Cory) can induce autophagy in neuronal cells, it remains unclear whether Cory has anti-tumor activities against pancreatic cancer.Methods: Assays of cell viability, EDU staining, TUNEL, colony formation, and flow cytometry were used to evaluate the effects of Cory on pancreatic cancer. Quantitative PCR and Western blot were used to evaluate the levels of mRNA and protein, respectively. In vivo anti-tumor efficacy was determined by HE staining, immunostaining, and Western blot.Findings: Cory dramatically inhibited cell proliferation, induced endoplasmic reticulum stress (ER stress), and triggered apoptosis in pancreatic cancer cell lines. Inhibition of ER stress by knocking down CHOP significantly alleviated the Cory-induced apoptosis. Cory induced cell death by elevating reactive oxygen species (ROS) production and activating p38. Pretreatment of the pancreatic cancer cells with ROS scavenger N-acetylcysteine and p38 inhibitor SB203580 relieved the Cory-induced inhibition on cell growth. Cory remarkably blocked pancreatic tumor growth in vivo. Interpretation: Cory exerts an anti-tumor effect on pancreatic cancer by inducing ER stress-mediated apoptosis via ROS-p38 pathways. Cory may therefore be a promising candidate for pancreatic cancer therapy. Funding Information: The study is supported by the National Natural Science Foundation of China, Wenzhou Municipal Science and Technology Bureau and the Fundamental Research Funds for Wenzhou Medical University.Declaration of Interests: The authors declare that they have no conflict of interest.Ethics Approval Statement: The study protocols described herein were approved by the Institutional Animal Care and Use Committee of Wenzhou Medical University.