Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas.
Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas.
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DOI：
10.1111/cas.13695
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发表时间：
2018-08
期刊：
影响因子：
5.7
通讯作者：
Hirao A
中科院分区：
文献类型：
--
作者：
Vu HT;Kobayashi M;Hegazy AM;Tadokoro Y;Ueno M;Kasahara A;Takase Y;Nomura N;Peng H;Ito C;Ino Y;Todo T;Nakada M;Hirao A
自噬在肿瘤发生中起着关键作用，但自噬如何有助于癌细胞对化疗药物的反应仍然存在争议。为了研究自噬在恶性胶质瘤中的作用，我们使用CRISPR/CAS9敲除来自胶质母细胞瘤患者的肿瘤细胞中自噬体形成所必需的ATG 5基因。虽然ATG 5破坏抑制了自噬，但它并没有改变胶质瘤细胞的表型，也没有改变它们对替莫唑胺（一种用于胶质母细胞瘤患者治疗的药物）的敏感性。抗癌药物库的筛选鉴定了与对照相比对ATG 5敲除神经胶质瘤细胞显示更大功效的化合物。虽然几种选定的化合物，包括尼日利亚菌素和盐霉素，显着诱导自噬，有效的自噬诱导剂mTOR抑制没有表现出ATG 5依赖性细胞保护作用。与ATG 5缺乏组合的阿托霉素以通过Ca 2+螯合或CaMKK抑制减轻的方式协同抑制胶质瘤细胞的球状体形成，表明与自噬抑制组合，钙动员化合物有助于有效的抗癌治疗。与对照组相比，用尼日利亚菌素处理的ATG 5敲除细胞显示线粒体源性活性氧和凋亡增加，表明自噬保护胶质瘤细胞免受线粒体活性氧介导的损伤。最后，使用患者来源的异种移植模型，我们证明了氯喹，一种药理学自噬抑制剂，显著增强了本研究中选择的化合物的疗效。我们的研究结果提出了一种新的治疗策略，其中钙动员化合物与自噬抑制剂联合治疗胶质母细胞瘤患者。
Autophagy plays a critical role in tumorigenesis, but how autophagy contributes to cancer cells’ responses to chemotherapeutics remains controversial. To investigate the roles of autophagy in malignant gliomas, we used CRISPR/CAS9 to knock out the ATG5 gene, which is essential for autophagosome formation, in tumor cells derived from patients with glioblastoma. While ATG5 disruption inhibited autophagy, it did not change the phenotypes of glioma cells and did not alter their sensitivity to temozolomide, an agent used for glioblastoma patient therapy. Screening of an anticancer drug library identified compounds that showed greater efficacy to ATG5‐knockout glioma cells compared to control. While several selected compounds, including nigericin and salinomycin, remarkably induced autophagy, potent autophagy inducers by mTOR inhibition did not exhibit the ATG5‐dependent cytoprotective effects. Nigericin in combination with ATG5 deficiency synergistically suppressed spheroid formation by glioma cells in a manner mitigated by Ca2+ chelation or CaMKK inhibition, indicating that, in combination with autophagy inhibition, calcium‐mobilizing compounds contribute to efficient anticancer therapeutics. ATG5‐knockout cells treated with nigericin showed increased mitochondria‐derived reactive oxygen species and apoptosis compared to controls, indicating that autophagy protects glioma cells from mitochondrial reactive oxygen species‐mediated damage. Finally, using a patient‐derived xenograft model, we demonstrated that chloroquine, a pharmacological autophagy inhibitor, dramatically enhanced the efficacy of compounds selected in this study. Our findings propose a novel therapeutic strategy in which calcium‐mobilizing compounds are combined with autophagy inhibitors to treat patients with glioblastoma.
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影响因子：
3.7
作者：
Lin CJ;Lee CC;Shih YL;Lin CH;Wang SH;Chen TH;Shih CM
通讯作者：
Shih CM
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
64.5
作者：
Mallilankaraman K;Doonan P;Cárdenas C;Chandramoorthy HC;Müller M;Miller R;Hoffman NE;Gandhirajan RK;Molgó J;Birnbaum MJ;Rothberg BS;Mak DO;Foskett JK;Madesh M
通讯作者：
Madesh M
影响因子：
--
作者：
Briceno, Eduardo;Calderon, Alejandra;Sotelo, Julio
通讯作者：
Sotelo, Julio
影响因子：
8.8
作者：
Cárdenas C;Müller M;McNeal A;Lovy A;Jaňa F;Bustos G;Urra F;Smith N;Molgó J;Diehl JA;Ridky TW;Foskett JK
通讯作者：
Foskett JK