自噬-溶酶体通路在HIF-1α抑制剂抗肿瘤活性中的作用机制

Tumor hypoxia, or fluctuating regions of low oxygen tension, is a dynamic feature of maligent tumor that is known to promote cancer progression, decrease response to therapy, and predict poor overall patient survival. As a result, demonstrating the complication regulation mechanisms of hypoxia and searching hypoxia-selective therapies have theoretical significance and practical needs. Autophagy, as an evolutionarily conserved catabolic process, is activated when the oxygen deprived, but the relationship between autophagy and key signaling molecules in hypoxia is poorly defined. In preliminary studies, we found the close relationship between the autophagy-lysosome pathway activation and the new HIF-1α inhibitor antitumor activity, which indicate the novel function ofthe autophagy-lysosome pathway which has not been identified.This aim of the project is to explore the autophagy-lysosome pathway regulation mechanism in hypoxia using a novel HIF-1α inhibitor Q6 as a probe. on the one hand, the purpose of the project is to investigate whether the autophagy pathway plays an indispensable role in mediating hypoxia signaling molecules HIF-1α degradation; on the other hand, the object of the project is to explore whether Q6-induced autophagy-lysosome pathway activation was a result of Q6-induced DNA damage. Obviously, all these efforts will not only benefit for finding new phenomenon of life and new anti-tumor molecular mechanism, but also provide a new horizon for the development of hypoxia-directed treatment.

低氧是实体瘤普遍存在的一个重要微环境，也是导致肿瘤细胞对放疗化疗耐受的重要原因，因此研究低氧应激通路中关键分子、开发靶向药物具有重大的现实意义。自噬-溶酶体通路与低氧肿瘤细胞的存活、凋亡和抗肿瘤药物耐受均关系密切，前期研究我们发现自噬溶酶体通路的激活与新型HIF-1α?抑制剂的抗肿瘤活性密切相关，提示该信号通路在低氧下发挥着未被探明的重要作用。本项目以新型HIF-1α抑制剂Q6为特异性分子探针，积极探索自噬-溶酶体信号通路在低氧下的调节机制，特别是由HIF-1α?抑制剂引起的自噬对HIF-1α?和其下游通路的调控，以及自噬-溶酶体通路的激活与其造成的DNA损伤之间的关系。鉴于这些信号转导和蛋白翻译后修饰在低氧抗肿瘤中的重要作用，通过研究这两条信号通路之间可能存在的调节机制，发现新的分子过程及抗肿瘤分子作用机理，并提供低氧抗肿瘤药物设计和研发的新思路具有十分深刻的意义。

缺氧是实体肿瘤微环境的主要特征之一，与肿瘤发展、浸润、转移等恶性生物学行为密切相关。缺氧诱导因子-1（HIF-1）为转录因子调控多种靶基因的表达，广泛参与哺乳动物细胞中缺氧诱导产生的特异性应答。在人体肿瘤中HIF-1a水平高低影响患者的预后，HIF-1a水平越高，肿瘤患者的病死率越高，其中尤以肝癌为甚。因此靶向HIF-1a已成为抗肿瘤药物研究的热点，但是目前尚缺乏有效手段介导缺氧环境中HIF-1a的降解。我们的研究发现小分子化合物Q6可在缺氧肿瘤细胞中启动自噬的发生，进一步通过促进p62和HIF-1a的结合，驱动HIF-1a出核发生降解。我们的研究首次揭示HIF-1a发生自噬通路降解的现象，为干预缺氧肿瘤提供了全新的策略和思路。