The DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Autophagy. 2010 Nov;6(8):1181-3. doi: 10.4161/auto.6.8.13367.
Metabolic and therapeutic stress activates several signal transduction pathways and releases damageassociated molecular pattern molecules (DAMPs) that regulate cell death and cell survival. The prototypical DAMP, high-mobility group box 1 protein (HMGB1) is released with sustained autophagy, late apoptosis and necrosis. Our recent findings reveal that the HMGB1 protein triggers autophagy or apoptosis in cancer cells, depending on its redox status. Reducible HMGB1 binds to the receptor for advanced glycation end products (RAGE), induces Beclin 1-dependent autophagy and promotes pancreatic or colon tumor cell line resistance to chemotherapeutic agents or ionizing radiation. In contrast, oxidized HMGB1 increases the cytotoxicity of these agents and induces apoptosis via the mitochondrial pathway. This suggests a new function for HMGB1 within the tumor microenvironment, regulating cell death and survival and suggests that it plays an important functional role in cross-regulating apoptosis and autophagy.
代谢和治疗应激激活了几种信号转导途径，并释放损伤相关分子模式分子 (DAMPs)，调节细胞死亡和细胞存活。高迁移率族蛋白 B1 (HMGB1) 是典型的 DAMPs，它在持续自噬、晚期凋亡和坏死时释放。我们最近的研究结果表明，HMGB1 蛋白根据其氧化还原状态在癌细胞中触发自噬或细胞凋亡。可还原的 HMGB1 与晚期糖基化终产物受体 (RAGE) 结合，诱导 Beclin 1 依赖性自噬，并促进胰腺或结肠肿瘤细胞系对化疗药物或电离辐射的耐药性。相比之下，氧化的 HMGB1 增加了这些药物的细胞毒性，并通过线粒体途径诱导细胞凋亡。这表明 HMGB1 在肿瘤微环境中具有新的功能，调节细胞死亡和存活，并表明它在调节细胞凋亡和自噬方面发挥着重要的功能作用。
