自噬增加与多发性骨髓瘤(MM)紧密相关，抑制自噬是治疗MM新策略。项目组首次发现石蒜碱(lycorine)能抑制自噬抵抗耐药发挥抗MM效应。且石蒜碱在蛋白水平下调胞核和胞质中HMGB1(高迁移率族蛋白1)，而HMGB1并非通过外泌途径减少。HMGBl在肿瘤中高表达，可从胞核转位至胞质与 Beclin 1作用，使得Beclin1从 Beclin1/Bcl-2复合物中解离出来而促进自噬，增强肿瘤细胞的耐药性。由此本项目提出科学假说：石蒜碱通过泛素化降解HMGB1，减少HMGB1与Beclin1结合，增加Beclinl/Bcl-2复合物抑制自噬抵抗耐药发挥抗MM的作用。探索HMGB1是否为石蒜碱关键效应分子, 研究石蒜碱下调HMGB1抑制MM自噬抵抗耐药的机制，有望阐明石蒜碱作用MM新机制，为发现MM治疗新靶标和新药物提供新策略。

Autophagy is closely related to the survival of multiple myeloma (MM) cells and becoming a new hot spot of MM therapy.We first demonstrated that lycorine had a selective anti-multiple myeloma (MM) effect via autophagy inhibition and the enhancing effect on the sensitivity to chemotherapy drugs in MM cell lines. Lycorine treatments resulted in significant decrease of high mobility group box 1 (HMGB 1) protein level both in cytoplasm and nucleus,which was not shown through exocytosis pathways.HMGB1 is univerally enriched in tumors,and functions by translocating to cytoplasm from the nuleus, then binding to Beclin1 and resulting in the releasing of Beclin1 from complex Beclin1-Bcl2,which finally induces autophagy and enhances drug resistance in some other tumor cell lines.In this study, we hypothesize that lycorine inhibits cells autophagy via ubiquitination degradation of HMGB1. HMGB1 degradation blocks formation of HMGB1-Bcl-2 complex and induces Bcl-2 combining with Beclin1.To prove these hypotheses, we intend to clarify the molecular signalings of autophagy inhibition introduced by lycorine and HMGB1 functions involved, and explore the potential key role of HMGB1 in autophagy supression targeted by lycorine. This study will further elucidate new molecular mechanisms of lycorine and posssibility of HMGB1 as a new target of MM therapy, to provide new prospect in MM treatment and medcine design.