title: Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway.
abstract: Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- and time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol-induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chien-Ju
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Ta-Liang
authors.initials: TL
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Yun
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Gong-Jhe
authors.initials: GJ
authors.lastname: Wu
authors.affiliation: Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Brain Disease Research Center, Taipei Medical University Wan-Fang Hospital, Taipei, Taiwan.
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Brain Disease Research Center, Taipei Medical University Wan-Fang Hospital, Taipei, Taiwan; Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan. Electronic address: rmchen@tmu.edu.tw.
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000633:toxicity*; D053148:Caspase 3 / Q000096:biosynthesis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005910:Glioma / Q000188:drug therapy*; D017705:Lignans / Q000633:toxicity*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000187:drug effects; D034741:RNA, Small Interfering / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis* / Q000187:drug effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000187:drug effects; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000225:Adenine; D001205:Ascorbic Acid; D001713:Biphenyl Compounds; D053148:Caspase 3; D017705:Lignans; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C480860:Map1lc3b protein, mouse; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C025946:3-methyladenine; C546842:MTOR protein, human
keywords: Autophagy; Honokiol; Malignant glioma; ROS; p53/PI3K/Akt/mTOR