期刊
CANCER SCIENCE
卷 109, 期 8, 页码 2497-2508出版社
WILEY
DOI: 10.1111/cas.13695
关键词
autophagy; calcium signaling; drug screening; glioblastoma; mitochondria
类别
资金
- Japan Society for the Promotion of Science [16H01199, JP17K07160]
- Ministry of Education, Culture, Sports, Science and Technology [15H02361]
- Japan Agency for Medical Research and Development [18cm0106104h0003]
- Grants-in-Aid for Scientific Research [16H01199, 15H02361] Funding Source: KAKEN
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据