恶性胶质瘤中溶酶体膜完整性靶向溶酶体膜完整性的治疗优势,Cancer Science

当前位置： X-MOL 学术 › Cancer Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

恶性胶质瘤中溶酶体膜完整性靶向溶酶体膜完整性的治疗优势
Cancer Science ( IF 4.5 ) Pub Date : 2022-06-03 , DOI: 10.1111/cas.15451
Yongwei Jing ₁ , Masahiko Kobayashi ₁ , Ha Thi Vu ₁ , Atsuko Kasahara _{2,

3} , Xi Chen ₁ , Loc Thi Pham ₁ , Kenta Kurayoshi ₁ , Yuko Tadokoro _{1,

3} , Masaya Ueno _{1,

3} , Tomoki Todo ₄ , Mitsutoshi Nakada ₅ , Atsushi Hirao _{1,

3}

Affiliation

溶酶体作为细胞的消化系统发挥作用，参与大分子循环、囊泡运输、代谢重编程和促生长信号传导。尽管溶酶体生物发生的质量控制被认为是癌症治疗的潜在目标，但尚未建立实用的策略。在这里，我们表明溶酶体支持的溶酶体膜完整性是一种针对受损溶酶体的选择性自噬，是胶质母细胞瘤 (GBM) 的一个有前途的治疗靶点。在这项研究中，我们发现艾芬地尔（一种 FDA 批准的具有神经调节活性的药物）与自噬抑制相结合，可有效抑制患者来源的 GBM 细胞的球状体形成。艾芬地尔增加细胞内 Ca ²⁺水平，导致线粒体活性氧介导的细胞毒性。艾芬地尔诱导的 Ca ²⁺升高是由于溶酶体释放 Ca ²⁺而不是内质网释放，这与作为溶酶体膜损伤指标的半乳糖凝集素 3 点状相关。作为 Ca ²⁺ATG5缺乏增强了释放，自噬保护免受溶酶体膜损伤。通过对 765 种 FDA 批准的化合物的比较分析，我们确定了除艾芬地尔之外的另一种临床可用的中枢神经系统 (CNS) 疾病药物阿莫沙平。这两种化合物都促进了溶酶体膜蛋白的降解，表明溶酶体在溶酶体膜完整性质量控制中的关键作用。重要的是，艾芬地尔和氯喹（一种临床可用的自噬抑制剂）对球状体形成的协同抑制作用在 GBM 细胞中是显着的，但在未转化的神经祖细胞中则不然。最后，在患者来源的异种移植模型中，氯喹显着增强了化合物诱导溶酶体膜损伤的作用。

"点击查看英文标题和摘要"

Therapeutic advantage of targeting lysosomal membrane integrity supported by lysophagy in malignant glioma

Lysosomes function as the digestive system of a cell and are involved in macromolecular recycling, vesicle trafficking, metabolic reprogramming, and progrowth signaling. Although quality control of lysosome biogenesis is thought to be a potential target for cancer therapy, practical strategies have not been established. Here, we show that lysosomal membrane integrity supported by lysophagy, a selective autophagy for damaged lysosomes, is a promising therapeutic target for glioblastoma (GBM). In this study, we found that ifenprodil, an FDA-approved drug with neuromodulatory activities, efficiently inhibited spheroid formation of patient-derived GBM cells in a combination with autophagy inhibition. Ifenprodil increased intracellular Ca²⁺ level, resulting in mitochondrial reactive oxygen species–mediated cytotoxicity. The ifenprodil-induced Ca²⁺ elevation was due to Ca²⁺ release from lysosomes, but not endoplasmic reticulum, associated with galectin-3 punctation as an indicator of lysosomal membrane damage. As the Ca²⁺ release was enhanced by ATG5 deficiency, autophagy protected against lysosomal membrane damage. By comparative analysis of 765 FDA-approved compounds, we identified another clinically available drug for central nervous system (CNS) diseases, amoxapine, in addition to ifenprodil. Both compounds promoted degradation of lysosomal membrane proteins, indicating a critical role of lysophagy in quality control of lysosomal membrane integrity. Importantly, a synergistic inhibitory effect of ifenprodil and chloroquine, a clinically available autophagy inhibitor, on spheroid formation was remarkable in GBM cells, but not in nontransformed neural progenitor cells. Finally, chloroquine dramatically enhanced effects of the compounds inducing lysosomal membrane damage in a patient-derived xenograft model. These data demonstrate a therapeutic advantage of targeting lysosomal membrane integrity in GBM.

更新日期：2022-06-03

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南