gms | German Medical Science

64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

26. - 29. Mai 2013, Düsseldorf

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Chloroquine affects chromatin structure and sensitizes stem-like glioma cells to ionizing radiation

Meeting Abstract

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  • Ella L. Kim - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz
  • Anne Rupp - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz
  • Gabriela Salinas-Riester - The Transcriptome Analysis Laboratory, University Medical Centre Göttingen, Göttingen
  • Darius Kalasauskas - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz
  • Mirjam Renovanz - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz
  • Bettina Sprang - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz
  • Marina Janocha - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz
  • Walter Schulz-Schaeffer - Department of Neuropathology, University Medical Centre Göttingen, Göttingen
  • Alf Giese - The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University, Mainz

Deutsche Gesellschaft für Neurochirurgie. 64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC). Düsseldorf, 26.-29.05.2013. Düsseldorf: German Medical Science GMS Publishing House; 2013. DocMI.13.08

doi: 10.3205/13dgnc390, urn:nbn:de:0183-13dgnc3908

Veröffentlicht: 21. Mai 2013

© 2013 Kim et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.

Gliederung

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Objective: To explore the effects of chloroquine on glioma stem-like cells with mutant p53.

Method: Glioma stem-like cells (GCS) were derived from mutant p53273H-expressing glioma cell line G112. Gliomasphere cultures were maintained in Neurobasal medium (Invitrogen) supplemented with bFGF and EGF (10 and 20 ng/ml, respectively). Evaluation of the tumorigenic potential and radioresistance was perfomed in an orthotopic glioma mouse model (Nu/Nu, CharlesRiver). Self-renewal and phenotypic plasticity were evaluated by using the neurosphere assay and immunostaining in cultured GSCs or their xenograft derivatives. Genome-wide expression analyses were performed using the HuGene 1.0.ST array (Affymetrix). Several candidate genes identified through the array analyses have been validated by qRT-PCR and western blot.

Results: The most significant finding is that chloroquine (ClQ) sensitizes GSCs to ionizing radiation in vitro and in vivo. Genome-wide gene expression analyses revealed that ClQ induces dramatic changes in global gene expression patterns in GSCs. Among the genes whose expression is affected by ClQ, prime therapeutic targets Aurora A/B and TGF-beta2 have been identified in silico and validated by qRT-PCR and western blot. Chromatin immunoprecipitation (ChIP) analyses revealed that ClQ induces structural changes in the chromatin and affects the binding of several DNA binding proteins including mutp53 and ets-1.

Conclusions: Our results indicate that modulation of chromatin structure might be an important mechanism underlying antineoplastic effects of ClQ and provide the first evidence for the therapeutic potential of ClQ in overcoming radioresistance mediated by GSCs.