title: ILKAP, ILK and PINCH1 control cell survival of p53-wildtype glioblastoma cells after irradiation.
abstract: The prognosis is generally poor for patients suffering from glioblastoma multiforme (GBM) due to radiation and drug resistance. Prosurvival signaling originating from focal adhesion hubs essentially contributes to therapy resistance and tumor aggressiveness. As the underlying molecular mechanisms remain largely elusive, we addressed whether targeting of the focal adhesion proteins particularly interesting new cysteine-histidine-rich 1 (PINCH1), integrin-linked kinase (ILK) and ILK associated phosphatase (ILKAP) modulates GBM cell radioresistance. Intriguingly, PINCH1, ILK and ILKAP depletion sensitized p53-wildtype, but not p53-mutant, GBM cells to radiotherapy. Concomitantly, these cells showed inactivated Glycogen synthase kinase-3β (GSK3β) and reduced proliferation. For PINCH1 and ILKAP knockdown, elevated levels of radiation-induced γH2AX/53BP1-positive foci, as a marker for DNA double strand breaks, were observed. Mechanistically, we identified radiation-induced phosphorylation of DNA protein kinase (DNAPK), an important DNA repair protein, to be dependent on ILKAP. This interaction was fundamental to radiation survival of p53-wildtype GBM cells. Conclusively, our data suggest an essential role of PINCH1, ILK and ILKAP for the radioresistance of p53-wildtype GBM cells and provide evidence for DNAPK functioning as a central mediator of ILKAP signaling. Strategies for targeting focal adhesion proteins in combination with radiotherapy might be a promising approach for patients with GBM.
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hausmann
authors.affiliation: Section of Experimental Neurosurgery/Tumor Immunology, Department of Neurosurgery University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.|Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.|Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, 01328 Dresden, Germany.|German Cancer Consortium (DKTK), 01307 Dresden, Germany.|German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.|Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Eke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D002470:Cell Survival; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051747:DNA-Activated Protein Kinase; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human; C495901:TP53 protein, human; C497263:PRKDC protein, human; C426826:ILKAP protein, human
keywords: DNA repair; ILK; ILKAP; PINCH1; radioresistance