title: Importance of ROS-mediated autophagy in determining apoptotic cell death induced by physapubescin B.
abstract: Physapubescin B, a steroidal compound extracted from the plant Physalis pubescens L. (Solanaceae), has been reported to possess anti-cancer potential, whereas the molecular mechanism remains elusive. In this study, we first demonstrated that physapubescin B induced autophagy in human cancer cells based on the evidence that physapubescin B increased lipidation of microtubule-associated protein 1 light chain 3 (LC3) as well as number of GFP-LC3 puncta. We further examined the molecular mechanisms and found that physapubescin B enhanced the autophagic flux through promotion of reactive oxygen species (ROS)-mediated suppression of mammalian target of rapamycin complex I (mTORC1), the key negative regulator of autophagy. Additionally, excessive ROS caused by physapubescin B also induced p53-dependent apoptotic cell death. Furthermore, we provided evidence that inhibition of autophagy either by a chemical inhibitor or gene silencing promoted physapubescin B-induced apoptotic cell death, indicating that autophagy serves as a cell survival mechanism to protect cell death. Thus, our data provide a clue that inhibition of autophagy would serve as a novel strategy for enhancing the anti-cancer potential of physapubescin B.
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Guang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Chinese Traditional Medicine Hospital of Zhejiang Province, No. 54 You-Dian Road, Hangzhou 310006, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: han-ming_shen@nuhs.edu.sg.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China. Electronic address: dxia@zju.edu.cn.
authors.forename: Dajing
authors.initials: D
authors.lastname: Xia
mesh_terms: D000972:Antineoplastic Agents, Phytogenic; D001343:Autophagy; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054358:Withanolides; C586240:physapubescin B; D000076222:Mechanistic Target of Rapamycin Complex 1
keywords: Apoptotic cell death; Autophagy; MTORC1; Physapubescin B; ROS