title: Livin contributes to tumor hypoxia-induced resistance to cytotoxic therapies in glioblastoma multiforme.
abstract: OBJECTIVE
  Tumor hypoxia is one of the crucial microenvironments to promote therapy resistance (TR) in glioblastoma multiforme (GBM). Livin, a member of the family of inhibitor of apoptosis proteins, contributes antiapoptosis. However, the role of tumor hypoxia in Livin regulation and its impact on TR are unclear.
  
  
  METHODS
  Livin expression and apoptosis for tumor hypoxic cells derived from human glioblastoma xenografts or in vitro hypoxic stress-treated glioblastoma cells were determined by Western blotting, immunofluorescence imaging, and annexin V staining assay. The mechanism of hypoxia-induced Livin induction was investigated by chromatin immunoprecipitation assay and reporter assay. Genetic and pharmacologic manipulation of Livin was utilized to investigate the role of Livin on tumor hypoxia-induced TR in vitro or in vivo.
  
  
  RESULTS
  The upregulation of Livin expression and downregulation of caspase activity were observed under cycling and chronic hypoxia in glioblastoma cells and xenografts, concomitant with increased TR to ionizing radiation and temozolomide. However, knockdown of Livin inhibited these effects. Moreover, hypoxia activated Livin transcription through the binding of hypoxia-inducible factor-1α to the Livin promoter. The targeted inhibition of Livin by the cell-permeable peptide (TAT-Lp15) in intracerebral glioblastoma-bearing mice demonstrated a synergistic suppression of tumor growth and increased the survival rate in standard-of-care treatment with radiation plus temozolomide.
  
  
  CONCLUSIONS
  These findings indicate a novel pathway that links upregulation of Livin to tumor hypoxia-induced TR in GBM and suggest that targeting Livin using cell-permeable peptide may be an effective therapeutic strategy for tumor microenvironment-induced TR.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. Department of Biomedical Informatics, Asia University, Taichung, Taiwan. chhsiehcmu@mail.cmu.edu.tw shyu9428@gmail.com 075006@mail.fju.edu.tw.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.affiliation: Department of Neurology, Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan. Graduate Institute of Immunology, China Medical University, Taichung, Taiwan. chhsiehcmu@mail.cmu.edu.tw shyu9428@gmail.com 075006@mail.fju.edu.tw.
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
authors.affiliation: Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei, Taiwan. chhsiehcmu@mail.cmu.edu.tw shyu9428@gmail.com 075006@mail.fju.edu.tw.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; C419866:BIRC7 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D003606:Dacarbazine; D000077204:Temozolomide