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https://hdl.handle.net/2440/69953
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Type: | Journal article |
Title: | Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells |
Author: | Azad, A. Jackson, S. Cullinane, C. Natoli, A. Neilsen, P. Callen, D. Maira, S. Hackl, W. McArthur, G. Solomon, B. |
Citation: | Molecular Cancer Research, 2011; 9(12):1696-1707 |
Publisher: | Amer Assoc Cancer Research |
Issue Date: | 2011 |
ISSN: | 1541-7786 1557-3125 |
Statement of Responsibility: | Arun Azad, Susan Jackson, Carleen Cullinane, Anthony Natoli, Paul M. Neilsen, David F. Callen, Sauveur-Michel Maira, Wolfgang Hackl, Grant A. McArthur and Benjamin Solomon |
Abstract: | DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive β-galactosidase staining, G(2)-M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. |
Keywords: | Cell Line, Tumor Animals Humans Mice Mice, Nude Imidazoles Quinolines Multiprotein Complexes rho GTP-Binding Proteins Proteins RNA, Small Interfering Protein Kinase Inhibitors Transplantation, Heterologous DNA Repair Gene Expression Regulation, Neoplastic Radiation Tolerance Tumor Suppressor Protein p53 DNA-Activated Protein Kinase DNA Breaks, Double-Stranded Gene Knockdown Techniques Phosphatidylinositol 3-Kinases TOR Serine-Threonine Kinases Cell Cycle Checkpoints Mechanistic Target of Rapamycin Complex 1 Cellular Senescence Phosphoinositide-3 Kinase Inhibitors |
Rights: | ©2011 American Association for Cancer Research. |
DOI: | 10.1158/1541-7786.MCR-11-0312 |
Published version: | http://dx.doi.org/10.1158/1541-7786.mcr-11-0312 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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