TMIC-76. HUMANIN RELEASE FROM TUMOR ASSOCIATED MYELOID CELLS PROMOTES GLIOMA CHEMORESISTANCE
نویسندگان
چکیده
Abstract Transcriptomic screens of brain tumor (glioblastoma; GBM) parenchymal cells indicated supporting traits the GBM microenvironment, but largely excluded mitochondrially enriched gene-sets. Here, we show that a mitochondrial transcript contributes to therapy resistance. We inspected non-coding transcriptome human associated myeloid (GAM) and observed an upregulation ribosomal subunit MT-RNR2, which contains open reading frame for signaling peptide humanin. Immunohistology disclosed humanin was preponderant in GAM. In vitro assays with range stem-like (GSCs) revealed nanomolar concentrations can drive cell expansion chemoresistance temozolomide. A series genetic, pharmacological Western blotting experiments showed extracellular increased GSC viability via stimulation GP130/IL6ST receptor MAPK (Erk) activation. Humanin responsiveness subject inter-individual heterogeneity predominated high expression levels IL6ST subunit. Mechanistically, promoted ATR-dependent DNA-repair machinery GSCs induction DNA-clamp component HUS1. slice culture model containing microglia confirmed these observations. is absent from mouse brain. Exogenous delivery into orthotopic models or over-expression specifically secreted variant recapitulated findings. Blockade trimeric interleukin permeant, FDA-approved drug bazedoxifene blocked humanin-mediated vivo. Overall, identified clinically applicable compound together predictive marker prevent human-specific model.
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2022
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noac209.1119