Abstract
Macroautophagy (hereafter referred to as autophagy) can increase or decrease the amount of cell death in response to various stimuli. To test whether autophagy also controls the characteristics associated with dying cells, we studied tumor cell killing by epidermal growth factor receptor-targeted diphtheria toxin (DT-EGF). DT-EGF kills epithelial and glioblastoma tumor cells with similar efficiency but by different mechanisms that depend on whether the cells activate autophagy when treated with the drug. Dying cells in which autophagy is induced selectively release the immune modulator high-mobility group B1 (HMGB1) without causing lysis of the cell membrane and classical necrosis. Conversely, cells that are killed by DT-EGF where autophagy is blocked, activate caspases but retain HMGB1. These data suggest that it may be feasible to manipulate the immunogenicity of dying cells by increasing or decreasing autophagy.
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Abbreviations
- BHMT:
-
betaine homocysteine methyltransferase
- DT-EGF:
-
diphtheria toxin-EGF
- eEF2:
-
eukaryotic elongation factor 2
- ∣EGFR:
-
epidermal growth factor receptor
- GFP:
-
green fluorescent protein
- HMGB1:
-
high-mobility group B1
- LDH:
-
lactate dehydrogenase
- PARP:
-
poly ADP-ribose polymerase
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Acknowledgements
We thank Drs. A Yeudall, M Bianchi, T Yoshimori, N Mizushima, J Debnath, and P Dennis for providing critical reagents and Patrick O'Toole and Corinne Lowe for help with some experiments. Supported by NCI Grant CA111421.
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Thorburn, J., Horita, H., Redzic, J. et al. Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ 16, 175–183 (2009). https://doi.org/10.1038/cdd.2008.143
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DOI: https://doi.org/10.1038/cdd.2008.143
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