title: Cobalt chloride treatment induces autophagic apoptosis in human glioma cells via a p53-dependent pathway.
abstract: Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxia-induced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxia- and 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.
authors.affiliation: Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Bor-Chin
authors.initials: BC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan, R.O.C.
authors.forename: Jui-Tai
authors.initials: JT
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, R.O.C.
authors.forename: Shun-Tai
authors.initials: ST
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan, R.O.C.
authors.forename: Chung-Ching
authors.initials: CC
authors.lastname: Chio
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan, R.O.C.
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D003035:Cobalt / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016587:Antimutagenic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003035:Cobalt; C025946:3-methyladenine; D002738:Chloroquine; D053148:Caspase 3; C018021:cobaltous chloride; D000225:Adenine; D020123:Sirolimus