Deregulated BCL-2 family proteins impact on repair of DNA double-strand breaks and are targets to overcome radioresistance in lung cancer.
J Cancer Res Clin Oncol
; 143(9): 1733-1744, 2017 Sep.
Article
en En
| MEDLINE
| ID: mdl-28432456
ABSTRACT
PURPOSE:
DNA damage-induced cell death is a major effector mechanism of radiotherapy. Aberrant expression of anti-apoptotic BCL-2 family proteins is frequently observed in lung cancers. Against this background, we studied radioresistance mediated by BCL-2 family proteins at the mechanistic level and its potential as target for radiochemotherapy.METHODS:
Lung cancer models stably expressing BCL-xL or MCL-1 were irradiated to study cell death, clonogenic survival, and DNA repair kinetics in vitro, and growth suppression of established tumors in vivo. Additionally, endogenous BCL-xL and MCL-1 were targeted by shRNA or pharmacologic agents prior to irradiation.RESULTS:
Radiation exposure induced apoptosis at negligible levels. Yet, anti-apoptotic BCL-xL and MCL-1 expression conferred short-term and long-term radioresistance in vitro and in vivo. Radioresistance correlated with pertubations in homologous recombination repair and repair of DNA double-strand breaks by error-prone, alternative end-joining. Notably, genetic or pharmacologic targeting of BCL-xL or MCL-1 effectively sensitized lung cancer cells to radiotherapy.CONCLUSIONS:
In addition to directly suppressing apoptosis, BCL-2 family proteins confer long-term survival benefits to irradiated cancer cells associated with utilization of error-prone repair pathways. Targeting BCL-xL and MCL-1 is an attractive strategy for improving lung cancer radiotherapy.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tolerancia a Radiación
/
Proteínas Proto-Oncogénicas c-bcl-2
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Reparación del ADN
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Neoplasias Pulmonares
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Cancer Res Clin Oncol
Año:
2017
Tipo del documento:
Article
País de afiliación:
Alemania