Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1696 - 1707 |
| Number of pages | 12 |
| Journal | Molecular Cancer Research |
| Volume | 9 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2011 |
| Externally published | Yes |
Cite this
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Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells. / Azad, Arun; Jackson, Susan; Cullinane, Carleen M; Natoli, Anthony L; Neilsen, Paul M; Callen, David Frederick; Maira, Sauveur-Michel; Hackl, Wolfgang; McArthur, Grant A; Solomon, Benjamin J.
In: Molecular Cancer Research, Vol. 9, No. 12, 2011, p. 1696 - 1707.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells
AU - Azad, Arun
AU - Jackson, Susan
AU - Cullinane, Carleen M
AU - Natoli, Anthony L
AU - Neilsen, Paul M
AU - Callen, David Frederick
AU - Maira, Sauveur-Michel
AU - Hackl, Wolfgang
AU - McArthur, Grant A
AU - Solomon, Benjamin J
PY - 2011
Y1 - 2011
N2 - 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 ?-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.
AB - 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 ?-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.
UR - http://mcr.aacrjournals.org/content/9/12/1696.full.pdf+html
U2 - 10.1158/1541-7786.MCR-11-0312
DO - 10.1158/1541-7786.MCR-11-0312
M3 - Article
VL - 9
SP - 1696
EP - 1707
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 12
ER -