Targeting HMGB1-mediated Autophagy in Cancer Therapy

描述（由申请人提供）：在常规癌症治疗期间，内在代谢以及外在治疗应激诱导癌细胞过表达损伤相关分子模式分子（DAMP）。它们增加释放到肿瘤微环境内的坏死或损伤区域中调节邻近和远处（全身性）组织中的细胞死亡（例如凋亡）和细胞存活（例如自噬）。原型DAMP，高迁移率族蛋白1（HMGB 1），是一种高度保守的核蛋白，具有多种细胞内和细胞外功能，包括转录调节和炎症和免疫调节。我们最近证明，HMGB 1是一个重要的调节自噬，细胞的分解代谢过程，促进细胞质成分的降解使用溶酶体机器。基于我们的研究结果，我们假设我们的中心假设是HMGB 1过表达和释放响应于癌症治疗激活自噬，从而增加对治疗的抵抗并促进肿瘤生长。为了验证这一假设，将利用遗传、生物化学和细胞生物学研究来表征HMGB 1是否以及如何通过自噬调节增加胰腺癌细胞对化疗剂如吉西他滨的抗性。特异性靶向HMGB 1的实验方法将利用我们创建的新型HMGB 1胰腺条件性敲除小鼠、HMGB 1中和抗体和HMGB 1特异性shRNA。该项目的长期目标是通过开发针对胰腺癌的新策略来改善接受癌症治疗的患者的结局，胰腺癌是一种与低生存率以及高度内在和/或获得性耐药相关的疾病。这些研究将为HMGB 1信号转导和自噬在肿瘤治疗中的作用提供新的见解。这种更深入的了解将用于提高现有胰腺癌治疗的有效性。

DESCRIPTION (provided by applicant): Intrinsic metabolic as well as extrinsic therapeutic stress during conventional cancer treatment induces cancer cells to overexpress Damage-Associated Molecular Pattern molecules (DAMPs). Their increased release into necrotic or injured regions within the tumor microenvironment regulates cell death (e.g. apoptosis) and cell survival (e.g. autophagy) in both adjacent and distant (systemic) tissues. The prototypic DAMP, High Mobility Group Box 1 (HMGB1), is a highly conserved nuclear protein with multiple intracellular and extracellular functions, including transcriptional regulation and modulation of inflammation and immunity. We recently demonstrated that HMGB1 is an essential regulator of autophagy, a cellular catabolic process that facilitates the degradation of cytoplasmic components using the lysosomal machinery. Based on our findings, we hypothesize that our central hypothesis is that HMGB1 overexpression and release in response to cancer therapy activates autophagy thereby increasing resistance to therapy and promoting tumor growth. To test this hypothesis, genetic, biochemical and cell biological studies will be utilized to characterize whether and how HMGB1 increases resistance of pancreatic cancer cells to chemotherapeutic agents such as gemcitabine through autophagic regulation. The experimental approach to specifically target HMGB1 will utilize novel HMGB1 pancreatic conditional knockout mice that we have created, HMGB1 neutralizing antibodies, and HMGB1 specific shRNA. The long term goal of this project is to improve the outcome of patients receiving cancer therapies by developing a novel strategy to target pancreatic cancer, a disease associated with low survival rates as well as a high degree of intrinsic and/or acquired resistance to therapy. These studies will provide new insights into HMGB1 signaling and the role of autophagy in tumor therapy. This deeper understanding will be used to improve the effectiveness of existing pancreatic cancer therapies.