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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Adaptor Proteins, Signal Transducing, Animals, Antineoplastic Agents, Alkylating, Apoptosis, Brain Neoplasms, Cell Hypoxia, Dacarbazine, Drug Resistance, Neoplasm, Gene Expression, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Inhibitor of Apoptosis Proteins, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasm Proteins, Promoter Regions, Genetic, Protein Binding, Temozolomide, Xenograft Model Antitumor Assays.
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Does livin contribute to tumor hypoxia-induced resistance to cytotoxic therapies in glioblastoma multiforme? Context: 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. 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. 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.
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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. Final Decision: yes