Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
Autophagy. 2011 Jan;7(1):112-4. doi: 10.4161/auto.7.1.14005. Epub 2011 Jan 1.
Damage-associated molecular pattern molecules (DAMPs) are cellularly derived molecules that can initiate and perpetuate immune responses following trauma, ischemia and other types of tissue damage in the absence of pathogenic infection. High mobility group box 1 (HMGB1) is a prototypical DAMP and is associated with the hallmarks of cancer. Recently we found that HMGB1 release after chemotherapy treatment is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia. Overexpression of HMGB1 by gene transfection rendered leukemia cells resistant to cell death; whereas depletion or inhibition of HMGB1 and autophagy by RNA interference or pharmacological inhibitors increased the sensitivity of leukemia cells to chemotherapeutic drugs. HMGB1 release sustains autophagy as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, degradation of p62 and accumulation of autophagosomes and autolysosomes. Moreover, these data suggest a role for HMGB1 in the regulation of autophagy through the PI3KC3-MEKERK: pathway, supporting the notion that HMGB1-induced autophagy promotes tumor resistance to chemotherapy.
损伤相关分子模式分子（DAMPs）是细胞来源的分子，在没有病原体感染的情况下，可在创伤、缺血和其他类型的组织损伤后引发和持续免疫反应。高迁移率族蛋白 B1（HMGB1）是一种典型的 DAMPs，与癌症的特征有关。最近我们发现，化疗治疗后 HMGB1 的释放是自噬的关键调节剂，也是白血病治疗干预的潜在药物靶点。通过基因转染过表达 HMGB1 可使白血病细胞对细胞死亡产生抗性；而通过 RNA 干扰或药理学抑制剂耗尽或抑制 HMGB1 和自噬可增加白血病细胞对化疗药物的敏感性。HMGB1 的释放通过微管相关蛋白 1 轻链 3（LC3）脂质化、LC3 向细胞质斑点的重新分布、p62 的降解以及自噬体和自溶体的积累来维持自噬。此外，这些数据表明 HMGB1 通过 PI3KC3-MEKERK：途径在自噬调控中发挥作用，支持 HMGB1 诱导的自噬促进肿瘤对化疗的耐药性这一观点。
