Cathepsin S-Nrf2环路通过线粒体钙单向转运体调控胶质母细胞瘤自噬与凋亡的机制研究

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in humans, however, the specific mechanisms of its development have not been well elucidated. Our previous studies have found that cathepsin S and NF-E2-related factor 2 (Nrf2) were overexpressed in glioblastoma and down-regulation of cathepsin S or Nrf2 could induce glioblastoma cell autophagy and apoptosis. And the results of preliminary experiment indicated that cathepsin S and Nrf2 regulated each other in glioblastoma cells. Meanwhile, we found that the activation of mitochondrial calcium uniporter (MCU) was related to down-regulation of cathepsin S or Nrf2-induced autophagy and apoptosis in glioblastoma cells. Based on our previous results and reviews over pertinent literature, we speculated that the crosstalk between cathepsin S and Nrf2 (Cathpsin S-Nrf2 loop) may exist in glioblastoma and MCU might play an important role in down-regulation of cathepsin S or Nrf2-induced autophagy and apoptosis. Therefore, we raised a hypothesis that “Cathepsin S-Nrf2 loop could regulate glioblastoma cell autophagy and apoptosis through activating MCU”. Based on preliminary studies, the relationship of cathepsin S and Nrf2 in glioblastoma and its role in glioblastoma prognosis, as well as the role of MCU in down-regulation of cathepsin S or Nrf2-induced autophagy and apoptosis would be further studied by molecular biological, methylation detection and transgenes technique both in vivo and in vitro. This study is source of innovation, which will provide new thread for effective therapy and new target for drug development.

胶质母细胞瘤是颅脑肿瘤中恶性程度最高的肿瘤，其发生发展机制仍不清楚。申请人前期研究已证实胶质母细胞瘤中cathepsin S和Nrf2表达增高，且下调cathepsin S或Nrf2可诱导细胞自噬和凋亡。预实验结果揭示胶质母细胞瘤内cathepsin S和Nrf2相互调控并且下调cathepsin S或Nrf2可通过线粒体钙单向转运体（MCU）诱导自噬和凋亡。基于1) Cathepsin S和Nrf2在胶质瘤内高表达；2) Cathepsin S和Nrf2相互调控，推测可能存在cathepsin S-Nrf2环路导致两者持续性激活，从而引起肿瘤恶性表型增加，而抑制该环路可以通过激活MCU来诱导肿瘤细胞自噬与凋亡。本项目基于前期研究基础，通过临床标本收集、体内外实验及分子生物学等相关技术，验证cathepsin S-Nrf2环路在胶质母细胞瘤内的作用。本研究属源头创新，可为临床治疗提供思路。

胶质母细胞瘤是颅脑肿瘤中恶性程度最高的肿瘤，其发生发展机制仍不清楚。申请人前期研究已证实胶质母细胞瘤中cathepsin S和Nrf2表达增高，且下调cathepsin S或Nrf2可诱导细胞自噬和凋亡。预实验结果揭示胶质母细胞瘤内cathepsin S和Nrf2相互调控并且下调cathepsin S或Nrf2可通过线粒体钙单向转运体（MCU）诱导自噬和凋亡。基于1) Cathepsin S和Nrf2在胶质瘤内高表达；2) Cathepsin S和Nrf2相互调控，推测可能存在cathepsin S-Nrf2环路导致两者持续性激活，从而引起肿瘤恶性表型增加，而抑制该环路可以通过激活MCU来诱导肿瘤细胞自噬与凋亡。本项目基于前期研究基础，通过临床标本收集、体内外实验及分子生物学等相关技术，验证cathepsin S-Nrf2环路在胶质母细胞瘤内的作用。本研究目前已发现在胶质母细胞瘤中存在cathepsin S-Nrf2环路，并且下调cathepsin S可以通过线粒体钙单向转运体来调控胶质母细胞瘤自噬和凋亡，为胶质瘤的治疗提供了新的思路，有可能会改善胶质瘤患者的预后。

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