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|Title:||Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells|
|Citation:||Molecular Cancer Research, 2011; 9(12):1696-1707|
|Publisher:||Amer Assoc Cancer Research|
|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; rho GTP-Binding Proteins; Proteins; RNA, Small Interfering; Protein Kinase Inhibitors; Transplantation, Heterologous; Cell Aging; 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; Cell Cycle Checkpoints|
|Rights:||©2011 American Association for Cancer Research.|
|Appears in Collections:||Medicine publications|
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