Halofantrine up-regulates ATP6V0D2 mediating cytotoxic autophagy in glioblastoma and its mechanism

Abstract

Background Halofantrine is a drug used to treat malaria, and recent studies have shown that it has potential to treat glioblastoma. Objective To study the inhibitory effect of Halofantrine on glioblastoma and its mechanism. Methods Based on GEO database and clinical samples, the expression difference of ATP6V0D2 gene in glioblastoma was detected. The inhibitory effect of Halofantrine on U251 cells and the expression of ATP6V0D2 gene and autophagy protein at gene and protein levels were detected in vitro. The importance of ATP6V0D2 gene was verified by constructing stable overexpression and overexpression model of ATP6V0D2 gene in U251 cells. The inhibitory effect and mechanism of Halofantrine on axillary tumor model in nude mice were verified in vivo. Results ATP6V0D2 gene was expressed in low level in glioblastoma patients. Halofantrine up-regulates ATP6V0D2 gene mediated U251 cytotoxic autophagy. After ATP6V0D2 knockdown, Halofantrine-mediated cytotoxic autophagy of U251 was inhibited, while overexpression was reversed. In addition, Halofantrine has a good anti-GBM effect in vivo, and its mechanism of action is consistent with in vitro experiments. Conclusion Halofantrine can mediate toxic autophagy of U251 cells through up-regulation of ATP6V0D2. ATP6V0D2 is a key tumor suppressor gene in glioblastoma.