Autophagy regulates selective HMGB1 release in tumor cells that are destined to die.
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.
Department of Pharmacology, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
J
J
Thorburn
H
H
Horita
J
J
Redzic
K
K
Hansen
A E
AE
Frankel
A
A
Thorburn
D001343:Autophagy / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D004167:Diphtheria Toxin; D024243:HMGB1 Protein; D007155:Immunologic Factors; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor