Targeting CREB-binding protein overrides LPS induced radioresistance in non-small cell lung cancer cell lines
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Mira Y. Gökyildirim1, Ulrich Grandel1,5, Katja Hattar1, Gabriele Dahlem1, Elena Schuetz1, Florian H. Leinberger2, Fabian Eberle2, Ulf Sibelius1, Friedrich Grimminger1, Werner Seeger3,6, Rita Engenhart-Cabillic2,4, Ekkehard Dikomey2 and Florentine S.B. Subtil2,4
1Department of Internal Medicine IV/V, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany
2Department of Radiotherapy and Radiooncology, Philipps-University, Marburg, Germany
3Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany
4Department of Radiotherapy, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany
5Asklepios Klinik Lich, Lich, Germany
6Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Florentine S.B. Subtil, email: Florentine.Subtil@staff.uni-marburg.de
Keywords: lung cancer; X-irradiation; infection; LPS; CREB
Received: March 22, 2018 Accepted: June 04, 2018 Published: June 22, 2018
Non-small cell lung cancer (NSCLC) has a very poor prognosis even when treated with the best therapies available today often including radiation. NSCLC is frequently complicated by pulmonary infections which appear to impair prognosis as well as therapy, whereby the underlying mechanisms are still not known. It was investigated here, whether the bacterial lipopolysaccharides (LPS) might alter the tumor cell radiosensitivity. LPS were found to induce a radioresistance but solely in cells with an active TLR-4 pathway. Proteome profiling array revealed that LPS combined with irradiation resulted in a strong phosphorylation of cAMP response element-binding protein (CREB). Inhibition of CREB binding protein (CBP) by the specific inhibitor ICG-001 not only abrogated the LPS-induced radioresistance but even led to an increase in radiosensitivity. The sensitization caused by ICG-001 could be attributed to a reduction of DNA double-strand break (DSB) repair.
It is shown that in NSCLC cells LPS leads to a CREB dependent radioresistance which is, however, reversible through CBP inhibition by the specific inhibitor ICG-001. These findings indicate that the combined treatment with radiation and CBP inhibition may improve survival of NSCLC patients suffering from pulmonary infections.
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