Anti-proliferation of triple-negative breast cancer cells with physagulide P: ROS/JNK signaling pathway induces apoptosis and autophagic cell death

// Pei Yu 1, * , Chao Zhang 1, * , Cai-Yun Gao 1 , Ting Ma 1 , Hao Zhang 1 , Miao-Miao Zhou 1 , Yan-Wei Yang 1 , Lei Yang 1 and Ling-Yi Kong 1 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China * These authors have contributed equally to this work Correspondence to: Ling-Yi Kong, email: cpu_lykong@126.com Lei Yang, email: dorothy19802003@gmail.com Keywords: physagulide P, cell cycle arrest, apoptosis, autophagy, ROS/JNK Received: April 13, 2017 Accepted: June 05, 2017 Published: July 17, 2017 ABSTRACT Physagulide P (PP), a new natural compound, was isolated from Physalis angulate L. i n our laboratory. In this study, we demonstrated that PP potently suppressed cell proliferation by inducing G2/M phase arrest in MDA-MB-231 and MDA-MB-468 cells. Moreover, PP provoked apoptosis by decreasing the mitochondrial membrane potential and elevating the Bax/Bcl-2 protein expression ratio. The caspase inhibitor Z-VAD-FMK partly restore cell viability, suggesting that apoptosis plays as an important role in the anti-proliferative effect of PP. PP-treated cells also underwent autophagy, as evidenced by the formation of autophagosomes and the accumulation of LC3BII. Furthermore, the knockdown of LC3B reduced PP-induced cytotoxicity, indicating that autophagy played an anticancer effect. PP also induced the generation of reactive oxygen species (ROS) and resulted in c-Jun N-terminal kinases (JNK) activation. Accordingly, JNK siRNA significantly attenuated PP-triggered apoptosis and autophagy, and ROS scavengers almost completely reverse this apoptosis and autophagy. The ROS scavenger also blocked PP-induced G2/M phase arrest and the phosphorylation of JNK. Our results revealed that PP induced G2/M phase arrest, apoptosis and autophagy via the ROS/JNK signaling pathway in MDA-MB-231 and MDA-MB-468 cells. Therefore, PP is a promising candidate for the development of antitumor drugs for the treatment of triple-negative breast cancer.