Regulation of HMGB1 release by autophagy - PubMed (original) (raw)

Regulation of HMGB1 release by autophagy

Jacqueline Thorburn et al. Autophagy. 2009 Feb.

Abstract

The characteristics of tumor cell killing by an anticancer agent can determine the long-term effectiveness of the treatment. For example, if dying tumor cells release the immune modulator HMGB1 after treatment with anticancer drugs, they can activate a tumor-specific immune response that boosts the effectiveness of the initial treatment. Recent work from our group examined the mechanism of action of a targeted toxin called DT-EGF that selectively kills Epidermal Growth Factor Receptor-expressing tumor cells. We found that DT-EGF kills glioblastoma cells by a caspase-independent mechanism that involves high levels of autophagy, which inhibits cell death by blocking apoptosis. In contrast, DT-EGF kills epithelial tumor cells by caspase-dependent apoptosis and in these cells autophagy is not induced. These differences allowed us to discover that the different death mechanisms were associated with differences in the release of HMGB1 and that autophagy induction is required and sufficient to cause release of HMGB1 from the dying cells. These data identify a new function for autophagy during cell death and open up the possibility of manipulating autophagy during cancer treatment as a way to influence the immunogenicity of dying tumor cells.

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Figure 1

Figure 1

Autophagy-regulated release of HMGB1. Healthy tumor cells contain nuclear HMGB1 protein; when the cells are killed by DT-EGF, or perhaps other drugs, they can die by apoptosis, which involves caspase activation and cell fragmentation but little HMGB1 release. Or, they can die by necrosis, which involves abrupt lysis of the cell membrane and is associated with release of HMGB1. Alternatively, if autophagy is induced in the dying cells, the dying cells can selectively release HMGB1, through a mechanism that is associated with autophagosomes. Because HMGB1 release from dying tumor cells can lead to a tumor-specific immune response, autophagy manipulation may provide a way to improve cancer treatment by regulating the immunogenicity of dying tumor cells.

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