title: Nitric oxide induces apoptosis and autophagy; autophagy down-regulates NO synthesis in physalin A-treated A375-S2 human melanoma cells.
abstract: Physalin A is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has been used for the treatment of sore throat, hepatitis, eczema and tumors in China. Our previous study demonstrated that physalin A induced apoptosis and cyto-protective autophagy in A375-S2 human melanoma cells. Induction of reactive oxygen species (ROS) with physalin A triggered apoptosis. In this study, NO generated by physalin A induced apoptosis and autophagy in A375-S2 cells, since physalin A induced the expression of inducible nitric oxide synthase (iNOS) in the cells. Generation of NO partially promoted both apoptosis and autophagy in A375-S2 cells. NO suppressed mTOR expression, which led to autophagy induction. An autophagic inhibitor, 3-methyladenine (3MA) promoted NO production, while acceleration of autophagy with an autophagic agonist rapamycin repressed NO production, suggesting that autophagy and NO production form a negative feedback loop that eventually protects the cells from apoptosis. The results together with the previous study indicate apoptosis and autophagy induced by physalin A in A375-S2 cells; the autophagy, repressing production of reactive nitrogen species (RNS) and ROS, protects the cells from apoptosis.
authors: Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China; China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
authors: Hao
authors: H
authors: He
authors: China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
authors: Yong-Sheng
authors: YS
authors: Feng
authors: China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
authors: Ling-He
authors: LH
authors: Zang
authors: China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
authors: Wei-Wei
authors: WW
authors: Liu
authors: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, People's Republic of China.
authors: Li-Qin
authors: LQ
authors: Ding
authors: Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
authors: Li-Xia
authors: LX
authors: Chen
authors: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, People's Republic of China.
authors: Ning
authors: N
authors: Kang
authors: China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
authors: Toshihiko
authors: T
authors: Hayashi
authors: Institute for Clinical and Biomedical Sciences, Kyoto 603-8072, Japan.
authors: Shin-ichi
authors: S
authors: Tashiro
authors: Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University, Tokyo 194-8543, Japan.
authors: Satoshi
authors: S
authors: Onodera
authors: Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, People's Republic of China. Electronic address: fengqiu20070118@163.com.
authors: Feng
authors: F
authors: Qiu
authors: China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China. Electronic address: ikejimat@vip.sina.com.
authors: Takashi
authors: T
authors: Ikejima
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D054358:Withanolides; C574201:physalin A; D009569:Nitric Oxide
keywords: A375-S2 cells; Apoptosis; Autophagy; Nitric oxide; Physalin A; mTOR