Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas. Issue 8 (26th July 2018)

• Record Type: Journal Article
• Authors: Vu, Ha Thi; Kobayashi, Masahiko; Hegazy, Ahmed M.; Tadokoro, Yuko; Ueno, Masaya; Kasahara, Atsuko; Takase, Yusuke; Nomura, Naho; Peng, Hui; Ito, Chiaki; Ino, Yasushi; Todo, Tomoki; Nakada, Mitsutoshi; Hirao, Atsushi
• Is Part Of: Cancer science. Volume 109:Issue 8(2018)
• Page Start: 2497
• Page End: 2508
• Publication Date: 2018-07-26
• Subjects: autophagy -- calcium signaling -- drug screening -- glioblastoma -- mitochondria; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13695
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : 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 Ca 2+ 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. Abstract : While autophagy is known to play a critical role in tumorigenesis, how autophagy contributes to cancer cell responses to chemotherapeutics has been controversial. In this study, we have successfully established ATG5‐deficient tumor cells derived from patients with glioblastoma (GBM) by CRISPR/CAS9. Screening of chemical compound libraries with the GBM cells lacking autophagy revealed that combining a Ca 2+ mobilizer with the autophagy inhibitor remarkably suppresses tumor growth in vitro and in vivo, with potential for new therapeutics for patients with GBM.