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Radiother Oncol. 2013 Sep;108(3):415-21. doi: 10.1016/j.radonc.2013.06.037. Epub 2013 Jul 25.

The PERK/ATF4/LAMP3-arm of the unfolded protein response affects radioresistance by interfering with the DNA damage response.

Author information

1
Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, The Netherlands; Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.

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 AND METHODS:

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.

KEYWORDS:

Breast cancer; LAMP3; Radiation; Resistance; UPR

PMID:
23891100
DOI:
10.1016/j.radonc.2013.06.037
[Indexed for MEDLINE]

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