Anti-proliferation of triple-negative breast cancer cells with physagulide P: ROS/JNK signaling pathway induces apoptosis and autophagic cell death
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Pei Yu1,*, Chao Zhang1,*, Cai-Yun Gao1, Ting Ma1, Hao Zhang1, Miao-Miao Zhou1, Yan-Wei Yang1, Lei Yang1 and Ling-Yi Kong1
1Jiangsu 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
Ling-Yi Kong, email: [email protected]
Lei Yang, email: [email protected]
Keywords: physagulide P, cell cycle arrest, apoptosis, autophagy, ROS/JNK
Received: April 13, 2017 Accepted: June 05, 2017 Published: July 17, 2017
Physagulide P (PP), a new natural compound, was isolated from Physalis angulate L. in 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.
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