ILKAP, ILK and PINCH1 control cell survival of p53-wildtype glioblastoma cells after irradiation
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Christina Hausmann1, Achim Temme2, Nils Cordes1,3,4,5,6, Iris Eke1,7
1OncoRay – National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
2Section of Experimental Neurosurgery/Tumor Immunology, Department of Neurosurgery University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
3Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
4Helmholtz-Zentrum Dresden – Rossendorf, Institute of Radiooncology, 01328 Dresden, Germany
5German Cancer Consortium (DKTK), 01307 Dresden, Germany
6German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
7Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health/National Cancer Institute, Bethesda, MD 20892, USA
Nils Cordes, e-mail: [email protected]
Iris Eke, e-mail: [email protected]
Keywords: ILKAP, DNA repair, radioresistance, ILK, PINCH1
Received: June 09, 2015 Accepted: September 25, 2015 Published: October 07, 2015
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.
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