Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence.
Lung Cancer
; 81(2): 167-73, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23683497
ABSTRACT
Radiotherapy is routinely used for the treatment of lung cancer. However, the mechanisms underlying ionizing radiation (IR)-induced senescence and its role in lung cancer treatment are poorly understood. Here, we show that IR suppresses the proliferation of human non-small cell lung cancer (NSCLC) cells via an apoptosis-independent mechanism. Further investigations reveal that the anticancer effect of irradiation correlates well with IR-induced premature senescence, as evidenced by increased senescence-associated ß-glactosidase (SA-ß-gal) staining, decreased BrdU incorporation and elevated expression of p16(INK4a) (p16) in irradiated NSCLC cells. Mechanistic studies indicate that the induction of senescence is associated with activation of the p53-p21 pathway, and that inhibition of p53 transcriptional activity by PFT-α attenuates IR-induced tumor cell killing and senescence. Gain-of-function assays demonstrate that restoration of p53 expression sensitizes H1299 cells to irradiation, whereas knockdown of p53 expression by siRNA inhibits IR-induced senescence in H460 cells. Furthermore, treatment with Nutlin-3a, a small molecule inhibitor of MDM2, enhances IR-induced tumor cell killing and senescence by stabilizing the activation of the p53-p21 signaling pathway. Taken together, these findings demonstrate for the first time that pharmacological activation of p53 by Nutlin-3a can sensitize lung cancer cells to radiation therapy via promoting IR-induced premature senescence.
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Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Radiossensibilizantes
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Proteína Supressora de Tumor p53
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Senescência Celular
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Imidazóis
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article