Thorburn Jacqueline, Frankel Arthur E, Thorburn Andrew
Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora, Colorado 80010, USA.
Autophagy. 2009 Feb;5(2):247-9. doi: 10.4161/auto.5.2.7552. Epub 2009 Feb 5.
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.
抗癌药物杀伤肿瘤细胞的特性能够决定治疗的长期效果。例如，如果死亡的肿瘤细胞在用抗癌药物治疗后释放免疫调节剂高迁移率族蛋白B1（HMGB1），它们就能激活肿瘤特异性免疫反应，从而提高初始治疗的效果。我们团队最近的研究探讨了一种名为DT-EGF的靶向毒素的作用机制，该毒素能选择性杀伤表达表皮生长因子受体的肿瘤细胞。我们发现，DT-EGF通过一种不依赖半胱天冬酶的机制杀伤胶质母细胞瘤细胞，该机制涉及高水平的自噬，而自噬通过阻断凋亡来抑制细胞死亡。相比之下，DT-EGF通过依赖半胱天冬酶的凋亡杀伤上皮肿瘤细胞，且在这些细胞中不会诱导自噬。这些差异使我们发现，不同的死亡机制与HMGB1释放的差异相关，并且自噬诱导是导致HMGB1从死亡细胞中释放所必需且充分的条件。这些数据确定了自噬在细胞死亡过程中的一项新功能，并开启了在癌症治疗期间操纵自噬以影响死亡肿瘤细胞免疫原性的可能性。
