The PERK/ATF4/LAMP3-arm of the unfolded protein response affects radioresistance by interfering with the DNA damage response.
Radiother Oncol
; 108(3): 415-21, 2013 Sep.
Article
em En
| MEDLINE
| ID: mdl-23891100
ABSTRACT
BACKGROUND AND PURPOSE:
Lysosome-associated membrane protein 3 (LAMP3) is induced by the PKR-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-arm of the unfolded protein response (UPR) during hypoxia. LAMP3 has prognostic value in breast cancer patients treated with radiotherapy. Here, we specifically investigated the role of the PERK/ATF4/LAMP3-arm in the radiation response of breast cancer cells. MATERIAL ANDMETHODS:
Radiosensitivity of breast cancer cells was examined after siRNA-mediated knockdown of PERK, ATF4 and LAMP3. Activation of DNA damage repair proteins was evaluated by Western blotting and immunocytochemistry.RESULTS:
Knockdown of the PERK/ATF4/LAMP3-arm and chemical inhibition of PERK could radiosensitise MDA-MB-231 cells significantly. Western blot analysis of several DNA damage repair proteins showed that LAMP3 knockdowns had an attenuated DNA damage response after radiation compared to controls. γ-H2AX foci analysis revealed that LAMP3 knockdowns had a reduced number of positive cells after irradiation, indicating that their DNA damage repair signalling response is decreased. In addition, the effect of autophagy inhibition was examined and revealed a radiosensitising effect and the presence of residual γ-H2AX foci.CONCLUSIONS:
The PERK/ATF4/LAMP3-arm causes radioresistance of breast cancer cells by increasing DNA damage repair signalling. Inhibition of PERK and/or autophagy may sensitise tumours to radiotherapy.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Tolerância a Radiação
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Dano ao DNA
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Neoplasias da Mama
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EIF-2 Quinase
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Fator 4 Ativador da Transcrição
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Proteínas de Membrana Lisossomal
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Resposta a Proteínas não Dobradas
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Proteínas de Neoplasias
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article