小分子天然化合物促前列腺癌细胞衰老并调节其分泌体的机制研究

采用低剂量化疗药物诱导肿瘤细胞衰老能显著降低药物毒性、提高疗效，但衰老细胞分泌体中的促炎因子等成分对临近细胞的促增殖、侵袭转移等负面作用亟待解决，也为探索促衰老及分泌调节的新机制、寻找新型促衰老药物提供了思路。本课题在前期发现的促衰老化合物中，地钱素类联苄天然产物结构独特，毒性较低，显著诱导前列腺癌（PCa）、特别是PCa耐药细胞衰老，抑制Akt/mTOR活性、诱导内质网应激，而且其抗炎活性能降低衰老细胞IL6的分泌，但对衰老中常见的DNA损伤应答无显著影响，作用机制独特。本项目拟探索该类化合物促PCa细胞、PCa耐药细胞衰老的靶点、作用机制和对分泌体组分的调节作用：研究Akt/mTOR途径及上下游调控因子在促衰老中的作用、与内质网应激及其它信号网络的关联；分析分泌体的组成及促炎因子的调节机制；动物水平确定衰老细胞的成瘤能力、分泌体对肿瘤微环境的影响以及化合物促PCa衰老的药效作用。

The new treatment strategies which use low dose chemotherapy drugs induces tumor cellular senescence have significant advantages, but the senescent cells secretion composition such as proinflammatory factor which can promote the adjacent cells proliferation, invasion and metastasis also need to be overcome. Therefore, many effeorts have been made to explor novel prosenescent mechanisms and search for the new promising agents. We have previously identified Marchantins,naturally-occuring bisbibenzyls with unique structure and low toxicity, can target proteasome and induce autophagic cell death in prostate cancer (PCa) cells, and low concentration of the compounds can also significantly induce PCa cells senescence, especially in the PCa drug-resistant cells. The inhibition activity of Akt/mTOR, induction of endoplasmic reticulum stress also occur in this process, however, no significant alteration was observed in DNA damage response which is typically activated in senescent cells.More importantly, marchantins attenuate the IL-6 secretion in senescent PCa cell.The project will further clarify the target(s) and prosenescent mechanisms by which marchantins act on. Investigation will be focused on how chemicals induce senescence, the roles of AKT/mTOR signaling and its downstream targets in induction of senescence.Furthermore,the composition and the pathways that regulate senescence-associated secretory factors will be investigated in this project. Also, animal trials are used to address the impact of secretory factors on bystanders and tumor microenvirament. The above study will finally confirm the novel mechanisms of marchantin compounds induce senescence, and lay the foundation for screening the effective drugs to treat PCa ,and particularly, drug tolerance PCa in the future.