Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence

Abstract

Glioma is a common brain malignancy for which new drug development is urgently needed because of radiotherapy and drug resistance. Recent studies have demonstrated that artemisinin (ARS) compounds can display antiglioma activity, but the mechanisms are poorly understood. Using cell lines and mouse models, we investigated the effects of the most soluble ARS analogue artesunate (ART) on glioma cell growth, migration, distant seeding and senescence and elucidated the underlying mechanisms. Artemisinin effectively inhibited glioma cell growth, migration and distant seeding. Further investigation of the mechanisms showed that ART can influence glioma cell metabolism by affecting the nuclear localization of SREBP2 (sterol regulatory element-binding protein 2) and the expression of its target gene HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), the rate-limiting enzyme of the mevalonate (MVA) pathway. Moreover, ART affected the interaction between SREBP2 and P53 and restored the expression of P21 in cells expressing wild-type P53, thus playing a key role in cell senescence induction. In conclusion, our study demonstrated the new therapeutic potential of ART in glioma cells and showed the novel anticancer mechanisms of ARS compounds of regulating MVA metabolism and cell senescence.