Autophagy regulates selective HMGB1 release in tumor cells that are destined to die

Abstract

Macroautophagy (hereafter referred to as autophagy) can increase or decrease the amount of cell death in response to various stimuli. To test if autophagy also controls the characteristics associated with dying cells, we studied tumor cell killing by Epidermal Growth Factor Receptor (EGFR)-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 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.

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

“…Because of the decreased size of miR-218-expressing orthotopic lesions, we investigated the role of nonapoptotic cell death downstream of TMZ treatment. Loss of nuclear high-mobility group protein B1 (HMBG1) stain is a marker for autophagic, tumor cytolytic, or necrotic cell death (23)(24)(25)(26), and we observed a significant reduction in nuclear HMGB1 staining in miR-218-expressing, TMZ-treated tumors in both orthotopic models ( identify increased nonapoptotic cell death as a mechanism to explain the reduced tumor growth in miR-218-expressing tumors treated with TMZ. A cohort of mice with orthotopic U87-SCR and U87-218 tumors was treated with DMSO or TMZ and monitored until they exhibited evidence of neurological deficits, at which time they were killed.…”

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

“…This raises the attractive possibility that autophagy regulates (within the Hyp-PDT treated cancer cells) the "emission" of other unknown DC maturation-inducing factors. Here, HMGB1 3 and its recently found association with autophagy-based secretion (induced by epidermal growth factor receptor-targeted diphtheria toxin), 55 makes it a possible candidate. However, the fact that HMGB1 is susceptible to ROS-based inactivation [56][57][58] and that we did not detect a significant HMGB1 release from Hyp-PDT treated cancer cells in conditions where the release of other immune-modulatory molecules like HSPs was strongly detected, 9 makes HMGB1 an unlikely candidate in this ICD paradigm.…”

Consensus guidelines for the detection of immunogenic cell death

“…[198][199][200] The release of HMGB1 from cells succumbing to ICD requires the permeabilization of both the nuclear and plasma membranes, de facto constituting a post-mortem event. 3,41 Although autophagy has been proposed to contribute to the release of HMGB1 from dying cells, at least under some circumstances, 201 the molecular machinery that underlies this crucial manifestation of ICD has not yet been elucidated in detail. This said, extracellular HMGB1 is well known to mediate robust proinflammatory effects upon binding to several receptors on the surface of immune cells, including TLR2, TLR4 and advanced glycosylation end product-specific receptor (AGER, best known as RAGE).…”