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Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2α in caspase-3/7-deficient cells

Oncogene volume 29, pages 3241–3251 (2010)Cite this article

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Abstract

As apoptosis defects limit efficacy of anticancer agents, autophagy has been proposed as a novel strategy for radiotherapy enhancement. We previously showed that caspase-3/7 inhibition induces autophagy and promotes radiosensitivity in vitro and in vivo. Therefore, we further investigated the mechanism by which radiation triggers autophagy in caspase-3/7-deficient cells, and found the involvement of endoplasmic reticulum (ER) stress. The ER activates a survival pathway, the unfolded protein response, which involves ER-localized transmembrane proteins such as protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1 and activating transcription factor-6. In this study, we found that PERK is essential for radiation-induced autophagy and radiosensitivity in caspase-3/7 double-knockout cells. Irradiation of these cells increased expression of phosphorylated-eIF2α. Similar results were seen after administration of tunicamycin (TM), a well-known ER stressor. Importantly, we found that the administration of TM with radiation in MCF-7 breast cancer cells, which are lacking functional caspase-3 and relatively resistant to many anticancer agents, enhances radiation sensitivity. Our findings reveal ER stress as a novel potential mechanism of radiation-induced autophagy in caspase-3/7-deficient cells and as a potential strategy to maximize efficiency of radiation therapy in breast cancer.

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Acknowledgements

This work was supported in part by NCI 1R01 CA125842–01A1 and DOD BC030542.

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  1. Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

    K W Kim, L Moretti, L R Mitchell, D K Jung & B Lu

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  1. K W Kim
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  2. L Moretti
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  3. L R Mitchell
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  4. D K Jung
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Correspondence to B Lu.

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Kim, K., Moretti, L., Mitchell, L. et al. Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2α in caspase-3/7-deficient cells. Oncogene 29, 3241–3251 (2010). https://doi.org/10.1038/onc.2010.74

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