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Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells.

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.
AuthorsArun Azad, Susan Jackson, Carleen Cullinane, Anthony Natoli, Paul M Neilsen, David F Callen, Sauveur-Michel Maira, Wolfgang Hackl, Grant A McArthur, Benjamin Solomon
JournalMolecular cancer research : MCR (Mol Cancer Res) Vol. 9 Issue 12 Pg. 1696-707 (Dec 2011) ISSN: 1557-3125 [Electronic] United States
PMID22009179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Imidazoles
  • Multiprotein Complexes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proteins
  • Quinolines
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • DNA-Activated Protein Kinase
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • rho GTP-Binding Proteins
  • dactolisib
Topics
  • Animals
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line, Tumor
  • Cellular Senescence (drug effects, genetics)
  • DNA Breaks, Double-Stranded (radiation effects)
  • DNA Repair (drug effects)
  • DNA-Activated Protein Kinase (antagonists & inhibitors, genetics, metabolism)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Gene Knockdown Techniques
  • Humans
  • Imidazoles (pharmacology)
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Multiprotein Complexes
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors (pharmacology)
  • Proteins (antagonists & inhibitors, metabolism)
  • Quinolines (pharmacology)
  • RNA, Small Interfering (genetics)
  • Radiation Tolerance (drug effects)
  • TOR Serine-Threonine Kinases
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 (genetics, metabolism)
  • rho GTP-Binding Proteins (genetics, metabolism)

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